The Call of the Wild: What Can Be Learned from Studies of SIV Infection of Natural Hosts?
Shari Gordon1, Ivona Pandrea2, Richard Dunham1, Cristian Apetrei2, Guido Silvestri1
1Departments of Medicine and Microbiology and Immunology, and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA, and Yerkes National Primate Research Center of Emory University, Atlanta, GA, USA;
2Tulane National Primate Research Center and Tulane Health Sciences Center, Tulane University, New Orleans, LA.
Address correspondence to G.S. at:
Division of Infectious Diseases, and Emory Vaccine Center
Emory University School of Medicine
954 Gatewood Road NE, Atlanta, GA, 30329
Tel: 404-7128113
Fax: 404-7278199
Email: gsilves@rmy.emory.edu
1. Introduction
The HIV/AIDS pandemic, with an estimated 40 million people infected worldwide and several million AIDS-related deaths per year, represents one of the worst tragedies of the twentieth century. A series of pivotal studies established that HIV infection and AIDS in humans originated from multiple episodes of zoonotic transmission of CD4+ T cell-tropic lentiviruses infecting African monkey species and collectively defined as Simian Immunodeficiency Viruses (SIV) [1]. HIV-1, which is responsible for the overwhelming majority of AIDS cases in humans, derives from the chimpanzee (Pan troglodytes) virus SIVcpz [2, 3], while HIV-2 derives from SIVsmm, which naturally infects the sooty mangabey (SM, Cercocebus atys) [4-6]. Among the natural hosts for SIV, SMs are particularly relevant as SIVsmm was used to generate the various rhesus macaque (Macaca mulatta, RM)-adapted SIVmac viruses (e.g., SIVmac239, SIVmac251) that are often used for studies of AIDS pathogenesis and vaccines [6-9]. As shown in Table 1, more than 30 additional African monkey species are known to be naturally infected with SIV in the wild and in captivity, including mandrills, African green monkeys (AGMs), baboons, l'hoest monkeys, and numerous others (reviewed in [1]). SIV infection of natural hosts is common in the wild and in captivity, and appears to be acquired at the time of sexual maturity (i.e., between 2-4 years of age, see [10]). All primate lentiviruses identified thus far fall within a single phylogenetic lineage distinct from lentiviruses from other species of mammals [11]. Within this primate lentivirus radiation, each primate species is generally infected with a specific subtype of SIV, such that multiple strains from any host species form a monophyletic clade. An exception is the mandrill (Mandrillus sphinx) that harbors two phylogenetically divergent types of SIV [12, 13]. The key virological features of SIV infection of natural hosts will be discussed in the section "Virological features" of this Review.
A puzzling feature of SIV infection in natural host monkey species is an observed general lack of pathogenicity. In most natural host animals, transmission of virus is not followed by profound CD4+ T cell depletion or AIDS-defining illness even after many years of infection [1, 14-20]. In marked contrast, without antiretroviral treatment, most HIV-infected individuals become severely immunocompromised and develop AIDS within 2-10 years. In addition, experimental SIV infection of non-natural host Asian monkey species, such as RMs, pigtail macaques (PTM, Macaca nemestrina), stump-tailed macaques (STM, Macaca arctoides), and cynomolgus monkeys (CYM, Macaca fascicularis), results in the development of symptoms similar to those described in AIDS patients (simian AIDS), including the progressive loss of CD4+ T cells and infection with opportunistic pathogens (reviewed in [21]).
Enlarge table
An additional consistent and intriguing feature of natural SIV
infection is the presence of high levels of plasma viremia that in
many cases actually exceed the levels typically observed in
pathogenic HIV and SIV infections [15-20]. This unexpected
finding contrasts with the well-known observation that, in both
HIV-infected individuals and experimentally SIV-infected macaques,
higher levels of virus replication predict faster disease progression
[22-25]. At present, it is still unclear why SIV infection is
non-pathogenic in natural host monkey species while inducing
immunodeficiency in non-natural hosts (included in this definition
are humans, who have only recently become a host species). In
addition, it is not known whether SIV infection of natural hosts has
always been non-pathogenic or mildly pathogenic, or whether
present-day animals may derive from the survivors of an ancient
retroviral pandemic. As such, the lack of disease progression in
naturally SIV-infected monkeys may represent the favorable outcome of
many thousands of years of parallel co-evolution between SIVs and
their various natural host species. It is now widely recognized that
a better understanding of the mechanisms underlying the lack of
disease in natural hosts for SIV infection will likely provide
important clues as to the pathogenesis of AIDS in HIV-infected
individuals [26, 27]. The significance of this line of
research for future efforts to halt the AIDS pandemic cannot be
overstated.
In this review we will discuss the main virological, immunological, and clinical features of SIV infection of natural hosts, and will conclude by reviewing a series of pathogenic hypotheses that may explain the absence of disease progression in these animal species.
2. Epidemiology of natural SIV infection
2.1 Phylogeny of Old World monkeys.
The Old World monkeys (family Cercopithecidae) are divided into two subfamilies (Cercopithecinae and Colobinae) [28]. The Cercopithecinae subfamily is further divided into two tribes: Papionini and Cercopithecini. The Papionini tribe includes the two mangabey genera (Chlorocebus and Lophocebus), the baboons (Papio), mandrills and drills (Mandrillus), and gelada monkeys (Theropithecus), all from Africa, and the Asian genus, Macaca [29]. The Cercopitecini tribe comprises over 25 species, including three arboreal genera: Allenopithecus, Miopithecus, and Cercopithecus and three terrestrial genera: Erythrocebus, Chlorocebus and Cercopithecus lhoesti supergroup [28]. Altogether, there are over 25 species in the Cercopithecini tribe. Although a taxonomic consensus has not been reached yet, this primate classification is in agreement with the classification of SIVs in which specific genera (e.g., Cercopithecus, Miopithecus, Chlorocebus and C. l'hoesti) harbor a unique SIV lineage [30]. Monkey from the Colobinae subfamily (Colobus monkeys) are common in both Africa and Asia, in which SIVs have been isolated in the central African colobus-guereza and from the west African red colobus and olive colobus (genera Colobus, Piliocolobus, and Procolobus). It is interesting to note that the approximate equidistance among the major SIV lineages does not match the phylogenetic relationships of their hosts (Figure 1). Asian species of Old World monkeys (colobine and macaques), as well as some African species (such as baboons), do not carry a species-specific SIV, suggesting that the last common ancestor of the Old World monkeys was not infected by SIV 25 million years ago [31], and that the emergence of SIVs followed the infection, at a later time point, of one of the derived African species with a lentivirus from a non-primate source [32].
2.2 Prevalence of SIV infection in the wild.
SIV prevalence appears to be relatively high in African non-human
primate species. Studies of hundreds of wild-born AGMs, the most
numerous and geographically dispersed monkeys in Sub-Saharan Africa,
indicate that animals belonging to different subspecies
[i.e., vervet (Chlorocebus pygerythrus), grivet
(C. aethiops), tantalus (C. tantalus) and sabaeus
(C. sabaeus)] all demonstrate a prevalence of SIVagm
infection of 40-50% [33-35], independent of their geographic
origin [36]. SIVagm prevalence correlates with age
[37] and, consistent with a pattern of sexual transmission,
no infections were identified in very young monkeys [38].
Interestingly, AGMs from the Caribbean islands are not infected with
SIV, and this lack of infection has been attributed to the
importation, in the 17th and 18th centuries [39], of juvenile
animals from Africa. The alternative explanation that SIVagm was not
yet
Figure 1. Phylogenetic relationships among SIV types and HIV strains inferred from pol by neighbor-joining using the HKY model of nucleotide substitution. Numerous viral strains are known only based on small pol integrase fragments. This tree was designed to include the maximum number of strains, therefore is based on a relatively short fragment (522 sites after removing gaps). Phylogenetic clusters are groups of related viruses and are defined by high bootstrap values. The numbers to the left of nodes indicate percentage bootstrap replicates supporting the clade to the right; bootstraps results of 75% or greater are shown. The phylogeny is mid-point rooted. The scale indicates substitutions per site and refers to the horizontal branch lengths. The vertical branch lengths are for clarity only.
present in the African AGM population two centuries ago is highly improbable, although cannot be dismissed if considering that HIV-1 prevalence in East Africa already reached levels of 25-30% after only 50 years of epidemic evolution. Similarly high prevalence (25-60%) of SIV infection is found in feral SMs in Sierra Leone, with evidence that the major route of transmission in this species is also sexual [40-42]. The fact that the prevalence of SIVsmm infection is higher in adult monkeys than in juveniles [40] may explain why initial evaluations found a lower prevalence (4-8%) in mangabeys kept as pets, as they are known to be captured as juveniles [5, 40]. In the red-capped mangabeys, prevalence may be close to 22% [43, 44]. In wild mandrills from Gabon the prevalence of SIVmnd-1 infection was reported to be 76% [12], with the same age-dependence as observed in AGMs and mangabeys [12]. In Cercopitecini the prevalence is similar to that of AGMs, with 57% of l'Hoest monkeys (Cercopithecus lhoesti) [45], 28-59% of Syke's monkeys (Cercopithecus albogularis) [46-49], and 64% of blue monkeys (Cercopithecus mitis) infected [49]. Finally, in different Colobinae species the prevalence of SIV infection was found to be 28-46% [50, 51]. SIV infection is absent in Barbary macaques of the Gibraltar region (Macaca sylvanus) and Saudi Arabian baboons (Papio hamadrayas), suggesting that the emergence and cross-species transmission of SIVs in African non-human primates occurred after the separation of these two species from their sub-Saharan counterparts [52].
Of the anthropomorphic primates or pongids (i.e., great apes) only two subspecies of Central African chimpanzees (Pan troglodytes) are known to carry specific SIVcpz strains: P. t. troglodytes and P. t. schweinfurthii [3, 42, 53-59]. Although the prevalence rates seem to be significantly lower than AGMs, mangabeys, and mandrills, foci of SIVcpz infections have been identified within the endemic geographic area [54]. Infection has not been detected in P. t. verus (a west African subspecies) caught in the wild or bred in captivity [60] and only one case of SIVcpz infection was documented in P. t. vellorosus (SIVcpzCAM-4), but this occurred in captivity by transmission from an infected P. t. troglodytes (SIVcpzCAM-3) [57]. Whether SIV has become extinct or was never a pathogen in certain chimpanzee sub-species is not yet known. Sero-epidemiological studies have failed to produce evidence of SIV infection in gorillas (Gorilla gorilla) [33, 43] or bonobos (Pan paniscus) [61]. As these two species of apes are closely related to humans, knowledge of the potential effects of SIV infection in bonobos and gorillas might provide valuable clues concerning SIV zoonotic potential.
2.3 Routes of transmission.
The higher prevalence of SIV infection in adult animals described in AGMs, SMs, and mandrills suggests that the main transmission route in the wild is horizontal transmission through sexual contact as well as bites and scratches [37, 38] [10]. However, twenty-years of observation of the semi-free colony of mandrills at the Centre Internationale de Recherche Medicale (CIRM), in Franceville, Gabon did not reveal any sexual transmission [12, 62-64]. Two of the founder males infected with two different viral types (SIVmnd-1 and SIVmnd-2) [12] transmitted the infection to four offspring and four other males, respectively, following aggressive contacts for dominance [12, 65]. In captive monkeys, several cases of horizontal transmission resulting from bites have been described [15], in some instances resulting in cross-species transmission of SIV [57, 66].
Interestingly, transmission from mother to infant seems less frequent than transmission between adult animals, and no case of perinatal transmission has ever been detected in AGMs [67]. It should be noted, however, that mother-to-infant transmission can occur, as SIV infection has been observed, albeit rarely, in pet monkeys captured at very early ages [68]. In addition, mother-to-infant transmission was reported in captive mandrills in Gabon [62]. However, the mechanism(s) of SIVmnd mother-to-infant transmission (in utero, perinatally or via breast-milk) are unclear, and a prospective study failed to produce experimental mother-to-offspring transmission by breast-feeding [69].
2.4 Cross-species transmission: frequency, restriction factors, and clinical outcome.
An important but still unanswered question is whether other members of the SIV group of viruses, in addition to SIVcpz and SIVsmm, could cross the species barrier to humans, potentially causing new pandemic waves [1, 70]. Some authors have suggested that massive human exposure to SIV through bushmeat consumption could fuel the emergence of new HIV types [1]. Other authors propose that simple exposure to these viruses is necessary but not sufficient for the selection of a new HIV type with the capacity for sustained transmission in human populations [71, 72]. Cross-species transmission of SIVs between different species of non-human primates has clearly occurred, as demonstrated by the emergence of recombinant SIVs [12, 44, 73-76] which could only have been generated as a consequence of such cross-species transmission events. Also, clear evidence of SIV cross-transmission between different species of African non-human primates was observed in the wild [77-79] and in captivity [48]. Importantly, experimental cross-species transmission of SIVsmm to different macaque species resulted in the development of the macaque model for AIDS [7]. SIVagm, SIVlhoest and SIVsun have also been successfully transmitted and were each shown to be pathogenic in PTMs [80]. In other instances, experimentally transmitted SIVmnd-2, SIVrcm or SIVagm to RMs only resulted in acute replication that was promptly cleared by the macaque host [13, 81, 82]. The mechanism(s) governing cross-species transmission of SIVs are largely unknown, but certain host factors have recently been identified that confer resistance or susceptibility to infection. Although this field is in its early stages, data are rapidly accumulating that show that cross-species transmission of retroviruses can be effectively blocked by specific host factors and that viral adaptation may be needed for successful transmission in a new host. The role of vif in species-specificity of SIVs was understood after the identification of the vif cellular target, the cellular protein APOBEC3G, that is incorporated into the virion during the reverse transcription to deaminate the minus strand of viral DNA [83], resulting in inactivation [84-87] and/or degradation of the viral genome [88]. This vif activity is species-specific, with human APOBEC3G being inhibited by HIV-1 Vif but not by SIVagm Vif, whereas AGM APOBEC3G is inhibited by SIVagm Vif, but not by HIV-1 Vif [89]. The mechanism of this species-specificity is a single amino acid change in APOBEC3G, i.e., a aspartate to lysine in position 128 [89-91]. Interestingly, the functional interactions between APOBEC3G and Vif can be reversed; mutation D128K generates a human APOBEC3G that is no longer inhibited by HIV-1 Vif but is now inhibited by SIVagm Vif and vice versa [89-91]. Another host-restriction factor that has been described recently is based on the TRIM5alpha gene product, a member of the tripartite motif (TRIM) family of proteins that is present in the cytoplasmic bodies and whose function is still poorly understood. TRIM5alpha mediates the restriction to HIV replication in non-human primate species, most notably the rhesus macaques, by blocking infection after HIV-1 entry but before reverse-transcription, more specifically by modulating the uncoating of a retroviral capsid [92, 93].
3. Virology of SIVs
3.1 Primate lentiviruses.
SIVs belong to the Lentivirus genus of the Retroviridae, and are distinct from other retroviruses due to their complex structure with several accessory genes in addition to gag, pol and env. In particular, three accessory genes are specific for primate lentiviruses: vpr, vpx and vpu. All known lentiviruses are exogenous and can be found in many mammals, including cats, horses, goats, cattle and primates, where they may induce immunodeficiency, neurological disorders, arthritis and other diseases [94]. Some data exist regarding the genomic organization and virus-host interaction for lentiviruses infecting different mammalian hosts: feline immunodeficiency virus (FIV), caprine arthritis-encephalitis virus (CAEV), equine infectious anemia virus (EIAV) and bovine immunodeficiency virus (BIV). It is interesting to note that both BIV and FIV also appear to be non-pathogenic in natural hosts [94, 95].
3.2 Genomic organization of SIVs.
All primate lentiviruses contain the three structural retroviral genes (gag, pol, env), the long terminal repeats (LTRs) at each end of the genome, and five accessory genes (vif, vpr, nef, tat, rev). The presence of two other regulatory genes (vpx and vpu) is variable. Three patterns of genomic organization have been described for primate lentiviruses (Figure 2): (i) SIVagm, SIVmnd-1, SIVlhoest, SIVsun, SIVsyk, SIVcol, SIVasc and SIVdeb contain only 5 accessory genes (tat, rev, nef, vif and vpr) [31, 47, 51, 96-99]; (ii) SIVcpz, SIVgsn, SIVmon, SIVmus and SIVden share this genomic organization with the addition of a supplementary gene, vpu [100, 101]; (iii) SIVsmm, SIVrcm, SIVmnd-2 and SIVdrl genomes are characterized by the presence of the vpx gene [6, 12, 75, 102]. SIVmac and HIV-2, which originated from cross-species transmission from SMs, also carry vpx [103, 104]. HIV-1, which originated following cross-species transmission from chimpanzees [2, 105], is similar to group (ii) in that it also carries a vpu. For the remaining known viruses (SIVtal, SIVblu, SIVolc, SIVwrc, SIVasc, SIVagi), complete genomes are not available [49, 50, 98, 106, 107].
3.3 Phylogenetic clusters of SIV.
Within phylogenetic trees of mammalian lentiviruses, all SIVs
cluster as a single group, suggesting that all derive from a common
ancestor virus that existed more than 1 million years ago [32,
108]. Phylogenetic analysis of the available SIV strains is
complicated by the high sequence diversity and the frequency of
recombination events. While phylogenetic trees of SIVs are
traditionally presented with six clusters, recent studies have shown
that the definition of "pure" versus "recombinant" lineages is
primarily a matter of chronology [109]. The first clear
cluster of SIV includes viruses from guenons (Cerchopitecus).
These viruses share a number of important structural features,
indicating that their clustering resulted from an ancient lineage
that infected Cercopithecus monkeys in the distant past
[99]. The second cluster includes the SIVsmm from SMs [5,
6, 15, 40-42, 110-112] as well as its derivative viruses HIV-2
and SIVmac [6, 7, 113]. Multiple cross-species transmissions
from SMs to humans gave rise to HIV-2 groups A through H [1, 4,
5, 40, 114, 115], while experimental transmission of SIVsmm to
macaques resulted in the SIVmac viruses [116]. SIVmac
sequences can be traced to viruses that infected captive SMs at the
California National Primate Research Center (Davis, CA) [117,
118]. Interestingly, SIVsmm sequences from naturally infected SMs
from Liberia, Sierra Leone and the Cote d'Ivoire have revealed wide
genetic diversity [5, 40-42, 112]. The third cluster includes
SIVagm from the four species of AGMs (genus Chlorocebus)
[24, 36, 73, 119-123]. Since the four species of AGM are
infected with distinct viruses, it is believed that SIVagm has
evolved in a host-dependent fashion [73, 124, 125]. The
fourth cluster (SIVlhoest group) includes viruses isolated from the
L'Hoesti supergroup (C. lhoesti and C. solatus)
[45, 96, 126, 127] and mandrills (M. sphinx) [12,
97, 128]. The fifth cluster includes SIVcol from the mantled
colobus (C. guereza) [51], which is the first SIV
isolated from monkeys belonging to the Colobinae sub-family.
Finally, the sixth cluster was initially defined by SIVcpz and HIV-1.
When pol trees are constructed, this cluster also includes two
other divergent viruses, SIVrcm from red-capped mangabeys and
SIVmnd-2/SIVdrl from mandrills and drills north of the Ougoue river.
It was originally considered that SIVrcm carries a SIVcpz insert in
the pol-vif genes. However, more recently, with the
discovery of the SIVgsn/SIVmon/SIVmus group of viruses, all of them
carrying a vpu, it was postulated that SIVcpz is in fact a
recombinant virus (see below). Partial sequences from newly
discovered SIVs (SIVblu, SIVolc, SIVwrc, SIVasc, SIVagi) are not yet
assigned to a lineage. We wish to emphasize that phylogenetic
lineages are not superimposable on genomic types; as our under
Figure 2. Genomic types of simian immunodeficiency viruses (SIV). Each gene is represented by a rectangular box with the name inside. Arrows point to genes spread over 2 locations. The genomic group including HIV-1 and SIVcpz can be further divided in two groups based on the overlapping of the env and nef genes. This overlapping is observed for SIVgsn/SIVmon/SIVmus and SIVden but not SIVcpz/HIV-1 (boxed in grey).
standing of the phylogenetic relationships continues to be modified
with the addition of new strains. It may, in fact, be more effective
to consider the three types of primate lentiviruses based on the
genomic organization, as described above.
3.4 Recombinant viruses.
Recombination events may occur between different SIVs, as a result of cross-species transmission, as well as between different viral subtypes within the same species. The most critical recombination of SIVs appears to be that involving ancestors of the SIVrcm with the SIVgsn/SIVmus/SIVmon lineages, resulting in the origin of the chimpanzee SIVcpz [59, 74], whose cross-species transmission to humans created the HIV/AIDS pandemic [2, 3, 53-57, 100, 129-131]. Other SIVs originating from recombination events include SIVagm.sab (that contains SIVrcm-like fragments) and SIVmnd-2/SIVdrl (that has a mosaic structure partly related to SIVrcm and partly to SIVmnd-1 [12, 75]). Some recent studies suggest that SIVrcm (that has the genomic structure of SIVsmm/SIVmac/HIV-2 group [102], but contains fragments similar to SIVagm.Sab and SIVcpz [102] and therefore was initially considered a recombinant virus) might be a "pure" virus [74], meaning that other viruses showing similarities with SIVrcm sequences are likely recombinants [132]. As serological evidence of human infection with SIVmnd-2 was recently reported in Cameroon, it appears that SIVmnd-2/SIVdrl may be a threat for new cross-species transmissions to humans [12].
3.5 Co-receptor usage by SIVs.
In all studied instances, SIVs bind and infect cells using the same system of receptors used by HIV-1 consisting of CD4 and a chemokine co-receptors. The most relevant co-receptors for HIV-1 replication in vivo are CCR5 and CXCR4 [133], with about 50% of cases of progression to AIDS temporally associated with a switch in viral tropism from R5 ("macrophage" tropic) to X4 ("lymphocyte" tropic) viruses [133]. Most of the SIVs naturally infecting non-human primates in Africa use CCR5 as the main co-receptor [134, 135]. However, SIVmnd-1, SIVagm.sab and some of the SIVsmm may also use CXCR4, although no pathologic correlation has been described in the infected animals [136-138]. In the two cases of simian AIDS in a natural host of SIV infection (one SM and one mandrill) for which co-receptor usage has been tested, we failed to detect a switch in co-receptor usage associated with disease progression [139, 140]. Interestingly, an exception to the use of CCR5 or CXCR4 by natural hosts is represented by SIVrcm from the red-capped mangabey that uses CCR2b as the coreceptor for viral entry [141]. An intriguing explanation for this finding is that the CCR5 gene of red-capped mangabeys contains a 24 bp deletion making recognition of env by CCR5 impossible [141]. As such, this finding may constitute an example of convergent evolution with humans who possess the delta-32 mutation in the CCR5 gene. A virus related to SIVrcm, the SIVagi from the agile mangabey (Cercocebus agilis) also uses CCR2, despite the fact that all agile mangabeys tested thus far do not show any CCR5 gene deletion [107]. The close phylogenetic relationships between SIVrcm and SIVagi, corroborated by these biological properties, suggest that SIVagi derives from cross-transmission of SIVrcm [107, 132].
3.6 Dynamics of viral replication in natural hosts of SIVs.
In HIV-infected patients, levels of plasma viral load are an important indicator of disease progression [22, 142, 143]. In marked contrast, all studied examples of SIV infection in natural hosts (i.e., SIVsmm, SIVagm and SIVmnd-1) very rarely progress to AIDS, despite levels of viral replication during the chronic phase of infection that are as high, or even higher, than those observed in chronically HIV-1-infected individuals [15, 17-20, 111, 144-146]. While most studies of this nature were performed using captive animals, the only investigation of SIV viral load in wild animals showed similarly high levels of viral replication [20]. Longitudinal analyses of the dynamics of plasma viremia in naturally SIV-infected animals suggest that the level of viral replication is relatively constant over time [20, 140]. Interestingly, in the one naturally SIV-infected SM that progressed to AIDS the set point level of viral replication was higher than average [132, 139]. However, naturally SIV-infected AGMs display a range of viral replication, in both peripheral blood and lymph nodes, that is considerably wider than that observed in SMs or mandrills [17, 18, 20, 146, 147].
A series of recent studies investigated the early dynamics of SIV replication in experimentally SIV-infected natural hosts including SMs, AGMs, and mandrills [138, 145]. While these studies were based on a mode of infection that is clearly "non-natural", they are still of interest because they allowed the investigation of the early events of SIV infection in natural hosts, which are otherwise virtually impossible to study. Experimental SIV infection of natural hosts is characterized by a peak in viremia (106-109 copies/ml of plasma) occurring between 9-11 days post-infection [138, 145], followed by a sharp decline (1-2 logs) and attainment (in all tested models of infection- SIVsmm, SIVagm.sab92018, SIVagm.ver644, SIVmnd-1, and SIVmnd-2), of a chronically high level of viral replication that is similar to that observed in naturally infected animals [12, 18, 145, 146]. Interestingly, when two species of AGMs (Chlorocebus sabaeus and C. pygerythrus or vervets) are experimentally infected with their respective SIVagm viruses (SIVagm.sab92018 and SIVagm.ver644), SIVagm.ver644 infection of vervets consistently results in a lower peak viremia than SIVagm.sab92018 infection of C. sabaeus. The further observation of lower viremia in SIVagm.ver644-infected C. sabaeus than in SIVagm.sab92018-infected vervets suggests that, in AGMs, the profile of viral replication during primary infection may be dependent on the viral strain used for the infection, and not on the host species. [138]
The observation of high viremia during the usually non-pathogenic SIV infection of natural hosts is certainly puzzling, but is likely to represent the result of an evolutionary virus-host adaptation that allows maximal survival of the host in the presence of maximal virus replication. The exact mechanisms underlying this host-virus adaptation and, in general, the lack of disease progression in African monkeys that are naturally infected with SIV are not yet fully understood, and the available data and remaining questions will be discussed below. One clear finding, however, is that natural SIV infections, in contrast to pathogenic HIV infection of humans and SIV infection of non-natural hosts, are not associated with chronic high levels of immune activation, T cell turnover, and bystander T cell apoptosis [16, 18, 148].
4. Immunological features of natural SIV infection
4.1 Primary SIV infection of AGMs and mandrills.
To better understand the immunological features of the acute SIV infection of natural hosts, we have performed a series of experimental SIV infections of AGMs and mandrills [138, 145-147, 149, 150]. SIVagm.ver644 infection of vervets does not induce any change in CD4+ T cell count, while experimental SIVagm.sab92018 infection of C. sabaeus induces a significant CD4+ T cell decline during the first two weeks of infection [138]. In mandrills, experimental SIVmnd-1-infection induced a transient, moderate depletion of CD4+ T cells in both blood and lymph nodes at the peak of plasma viremia, while SIVmnd-2 infection resulted in only a slight reduction of CD4+ T cell percentages in the lymph nodes and not in the peripheral blood [146, 147]. Importantly, experimental SIV infection of both AGMs and mandrills sharply contrasts with the pathogenic SIVmac infection of macaques in that the CD4+ T cell counts in the natural hosts rebounded to pre-infection values soon after acute infection and remained stable throughout the chronic phase [138, 146].
An important component of the interaction between primate lentiviruses and the host immune system is the generation of a state of a chronic immune activation that is particularly evident in HIV-infected individuals and is thought to be a determinant of the AIDS-associated CD4+ T cell depletion. We investigated the kinetics of immune cell activation during experimental SIVagm-infection of AGMs and SIVmnd-2-infection of mandrills, and found that, in both species, an early increase in the fraction of activated CD4+ and CD8+ T cells is followed by the return to baseline levels of immune activation despite continuously high viremia in the chronic phase of SIV infection (103-106 RNA copies/ml plasma) [147, 149].
In a more recent study of the early immunological events following experimental SIVagm infection of AGMs, we focused our investigation on the cytokine production and FOXP3 expression. We observed a strong induction of TGF-b1 and FOXP3, followed by a significant increase in IL-10 expression in these AGMs. In sharp contrast to pathogenic lentiviral infections, we observed only a transient increase of IFN-g expression and no changes in the levels of TNF-a and MIP-1a/b expression following infection. These results, combined with the finding of an early increase in the levels of CD4+CD25+ T cells suggest that SIVagm infection of AGMs is associated with the rapid establishment of an anti-inflammatory environment which may prevent the host from developing the aberrant chronic T cell hyperactivation that is correlated with progression to AIDS during HIV-1 infection [149]. Taken together, these data further support the hypothesis of a protective role for the downregulation of T cell activation in natural hosts infected with species-specific SIVs. In particular, it is becoming clear that the establishment of anti-inflammatory profiles of gene expression early on in the immune response to SIV antigens is associated with protection against AIDS [149].
4.2 Immunology of natural SIV infection of SMs.
Immunological studies of the non-pathogenic SIV infection in natural host monkey species have been difficult to perform due to limited access to the animals and a lack of well-characterized immunological reagents. One of the best available resources to study non-pathogenic SIV infection in a natural host species is the large colony of naturally SIV-infected SMs of the Yerkes National Primate Research Center of Emory University (Atlanta). SIV-infected SMs from Yerkes colony, as well as animals from other smaller colonies, have been the object of several virological and immunological studies over the past few years [15, 16, 18, 139, 150-155], see Table 2.
Similar to other natural hosts, SIVsmm-infected SMs usually
maintain normal CD4+ T cell counts and very rarely develop AIDS
despite high levels of virus replication [15, 18, 144]. In a
recent report of a study undertaken to investigate the effects of
SIVsmm infection on the SM immune system, we described a
cross-sectional analysis of the lymphocyte phenotype and function in
29 SIV-infected and 19 uninfected SMs [18]. This analysis
showed that the SIVsmm-infected SMs maintain near normal CD4+
T cell counts in both blood and lymph nodes, and are characterized by
preserved function of their T lymphocytes [18]. Analysis of
the expression of markers of T cell activation, proliferation, and
apoptosis indicated that the SIVsmm-infected SMs show limited immune
activation and T cell apoptosis when compared to HIV-infected
individuals [18]. In particular, SIVsmm-infected SMs showed:
(i) only mild increases in the fraction of proliferating CD4+ T cells
in the blood, with normal levels of proliferating CD8+ T cells; (ii)
normal levels of proliferating CD4+ and CD8+ T cells in the lymph
nodes; (iii) normal production of pro-inflammatory cytokines by T
cells; (iv) a low frequency of apoptotic T cells in the lymph nodes;
and (v) normal in vitro susceptibility to apoptosis
[18]. In addition, we found that SIVsmm-infected SMs seem to
maintain a preserved T cell regenerative capacity, with normal bone
marrow morphology and function, normal levels of T-cell Receptor
Excision Circle (TREC)-expressing T cells, and preserved lymph node
architecture [18]. As we observed significant differences in
CD4+ T cell count between individual SIVsmm-infected SMs, we
investigated a potential correlation between increased T cell
activation and a trend towards CD4+ T cell depletion. By performing a
series of linear regression analyses, we discovered a significant
inverse correlation between CD4+ T cell count and the level of T cell
activation [18]. Taken together, these results support the
hypothesis that the absence of generalized immune activation in
SIVsmm-infected SMs is a mechanism that favors the preservation of
CD4+ T cell homeostasis. Consistent with this hypothesis are the
results of another study in which we inoculated three SMs and three
RMs with uncloned SIV derived from the plasma of an SIVsmm-infected
SM [150]. While high levels of virus replication were
observed in both species, only RMs developed chronic immune
activation and increased T cell apoptosis, with two out of three
animals sacrificed due to the development of simian AIDS within 2
years. In contrast, only minimal immune activation and T cell
apoptosis were observed in the three experimentally SIVsmm-infected
SMs that are all still alive and symptom-free after five years
[150]. It is important to note that the lack of chronic
immune activation in naturally SIVsmm-infected SMs that do not
progress to AIDS is consistent with the hypothesis that chronic
immune activation is a main determinant of disease progression during
HIV infection [156-159].
To collect a more comprehensive set of immunological data on SIVsmm-infected SMs we then conducted a cross-sectional survey of all 110 animals of the Yerkes colony [160]. Confirming our previous observations [18], we found no correlation between CD4+ T cell count and viral load, suggesting that the level of virus replication is not the main determinant of CD4+ T cell dynamics in SIVsmm-infected SMs. As natural SIVsmm infection of SMs typically occurs around the time of sexual maturity [10], age may be used as a surrogate marker for length of infection, but no correlation was found between CD4+ T cell count and age of the animals. Thus, it is unlikely that CD4+ T cell counts in those natural hosts is simply a reflection of the duration of infection in SIVsmm-infected SMs. As seen previously, though, [18], increased levels of T cell activation were significantly correlated with low CD4+ T cell counts. Importantly, this study led us to discover that while 85-90% of SIV-infected SMs exhibit the healthy levels of CD4+ T cells previously described [18], a subset (10-15%) of SIVsmm-infected SMs show significant CD4+ T cell depletion, i.e. <500 cells/mm3 [161]. Irrespective of their low CD4+ T cell counts, these SMs are still asymptomatic, although the recent description of a case of AIDS in a CD4-depleted, SIVsmm-infected SM at the Tulane Primate Center [139] suggests that this asymptomatic phase may be temporary, at least in some animals. It should be noted that we did not find a CD4+ T cell count of <500 in any of over thirty tested SIVsmm-uninfected SMs, indicating that the "CD4-low" phenotype is specific for SIVsmm-infected animals. This previously unrecognized phenotype (CD4"low") of the asymptomatic natural SIV infection of SMs may represent an "intermediate" outcome of infection between the typically pathogenic HIV infection of humans, and the vast majority of non-pathogenic SIVsmm infections of SMs that are characterized by normal CD4+ T cell counts. When compared to SIVsmm-infected "CD4-high" SMs, "CD4-low" animals show similar levels of viremia, a non-significant trend towards older age, and significantly increased expression of markers of T cell activation [162]. Interestingly, the two SIVsmm-infected SMs with the lowest CD4+ T cell counts (i.e., <50/mm3) showed normal levels of T cell activation, suggesting a complex pathogenesis for this relatively rare phenotype that likely involves viral as well as host factors [162]. A similar phenotype (i.e., very low CD4 count, no increase in T cell activation, and absence of clinical symptoms of AIDS) was also observed in two out of six SMs that were experimentally inoculated with uncloned SIVsmm [163]. Understanding why SIVsmm-infected SMs rarely develop AIDS symptoms even when their CD4+ T cell counts reach AIDS-defining levels could be helpful to delineate the mechanisms that cause the highly variable time to clinical manifestations of AIDS in CD4+ T cell-depleted HIV-infected patients.
4.3 Attenuated cellular immune responses to SIV in SMs.
A number of observations support the possibility that during pathogenic HIV and SIV infections the generation of HIV/SIV specific cellular immune responses, and in particular those mediated by CD8+ T cells, may protect from disease progression (reviewed in [164]). By contrast, it has been proposed that the prevailing level of immune activation in HIV-infected humans, which is at least partly dictated by HIV-specific cellular immune responses, plays a role determining the loss of CD4+ T cell homeostasis [156-159]. To better understand the nature of the interaction between host cellular immune responses and disease progression during retroviral infections, we systematically analysized the SIV-specific T cell responses in naturally SIVsmm-infected SMs [161]. We measured the magnitude and breadth of the SIV-specific responses in both CD3+CD8+ and CD3+CD8- (i.e., predominantly CD4+) T cells in all 110 SIV-infected SMs of the Yerkes colony, and investigated whether a relationship exists between the magnitude or breadth of these responses and the markers of disease progression (i.e., viral load and CD4+ T cell count). We found that while SIV-specific T cell responses can be detected in the majority of naturally SIVsmm-infected SMs, their magnitude is generally lower than what has been described, using the same technique, in HIV-infected patients [165]. In addition, no correlation was found between either breadth or magnitude of SIV-specific T cell responses and either viral load or CD4+ T cell count. It is interesting to note that the magnitude of the SIV-specific cellular responses did not appear to determine the level of T cell activation and proliferation in SIVsmm-infected SMs. Taken together, these results indicate that: (i) the presence of a strong and broadly reactive T cell response to SIV antigens is not a requirement for the lack of disease progression in SIVsmm-infected SMs; and also the converse, that: (ii) the complete suppression of SIV-specific T cell responses (i.e., immunologic tolerance and/or ignorance) is not required for the low levels of T cell activation that are likely instrumental in avoiding AIDS in these animals [161]. It would be interesting to know what genetic factors (i.e., different MHC and KIR alleles) are involved in determining the variability in the level of cellular responses to the virus in naturally SIV-infected monkeys- in particular in SMs, However, the most important implication of this study concerns the nature of the evolutionary co-adaptation of SIVs and their natural host monkey species, and indicates clearly that SMs, and perhaps other natural hosts for SIV as well, have adapted to the selective pressure of SIV infection and reached a disease-free state without the generation of a strong and broadly reactive antiviral cellular immune response. Instead, a general attenuation of the SIV-specific T cell responses appears to be a favorable evolutionary trait. It is tempting to speculate that this host-virus adaptation that results in low levels of SIV-specific cellular immune responses reflects the extreme elusiveness of SIV as a target for immunity. In this regard, these studies of the immunological features of SIVsmm infection in natural hosts emphasizes the tremendous challenge of artificially inducing, with an AIDS vaccine, a type of protective immunity that has not been selected for in many thousands years of evolutionary pressure posed by retroviruses on the primate immune system.
4.4 HIV and SIVcpz infection of chimpanzees.
Chimpanzees are the closest relatives of humans that are known to be natural hosts for SIV infection [1], and, in contrast to other non-human primates, can also be experimentally infected with HIV-1. For both budgetary and ethical reasons experiments involving HIV-1 infection of captive chimpanzee have been infrequently carried out. At this time approximately 150 chimpanzees have been experimentally infected with HIV-1 and only one chimpanzee infected with multiple strains of HIV was reported to progress to AIDS [166]. This lack of disease progression may or may not be due to the fact that, unlike SIVcpz during natural infection, HIV-1 does not replicate well in chimpanzees [59, 167, 168]. Of the chimpanzees that were infected with HIV-1 at the Yerkes Primate Center, three animals showed evidence of CD4+ T cell decline with less than 200 cells/mm3 of peripheral blood without clinical signs of AIDS [169]. Interestingly, disease progression in these animals was associated with elevated HLA DR and CD38 expression on CD8+ T cells, loss of naïve CD45RA+ T cells, and a significantly increase in CD29+ memory CD8+ T cells [169]. To the contrary, low levels of T cell activation and bystander apoptosis were found in HIV-infected chimpanzees with no evidence of immunodeficiency [170-172]. The presence of an activated phenotype in the HIV-1-infected chimpanzees that show CD4+ T cell depletion is again consistent with a pathogenic role of the chronic immune activation during HIV/SIV infections. While only limited data are available on the immunological features of natural SIVcpz infection of chimpanzees, it appears that the infection is non-pathogenic in these animals, with absence of AIDS-like symptoms, preserved CD4+ T cell counts and absence of either chronic T cell activation or increased T cell susceptibility to apoptosis (Reviewed in [59]). It is hoped that further studies of the immunological features of natural SIVcpz infection of chimpanzees will be carried out in the future, as a better understanding of the virological and phylogenetic similarities between HIV-1 and SIVcpz and their association with apparently divergent infection outcomes of humans and chimpanzee, respectively, may help elucidate the mechanisms of AIDS pathogenesis.
5. Progression to AIDS in natural hosts for SIV infection.
For many years, it was believed that SIV infection was never pathogenic in their natural African primate hosts. As perhaps expected, given the natural variability of infection outcomes in this large outbred population with great genetic diversity, a number of cases of AIDS-like illnesses in natural hosts for SIV infection have recently been described. Studying these rare cases of AIDS (as well as the instances of CD4+ T cell loss without AIDS observed in naturally SIV-infected SMs) may aid in the identification of virus and host factors that influence the development of progressive immunodeficiency after infection with primate lentiviruses.
As shown in Table 3, occurrence of an AIDS-like disease has now been reported in mandrills infected with SIVmnd-1 and SIVmnd-2 [12, 140] in SMs infected with SIVsmm [139, 173], and in one AGM co-infected with SIVagm and STLV [174]. Moreover, AIDS has resulted in African non-human primates after infection with heterologous virus, including baboons infected with HIV-2 [175], a subset of chimpanzees infected with HIV-1 [169, 175, 176], and a black mangabey infected with SIVsmm [177]. As mentioned above, these cases involve a very small minority of animals, and thus represent a rare occurrence. Interestingly, the animals that develop simian AIDS show a consistent pattern of disease progression that appears to be characterized by levels of viremia that are significantly higher than those observed in the majority of the non-progressor monkeys [132]. In all cases of natural SIV infection that progressed to AIDS, the incubation period was very long (>15 years) and, in fact, approximated or even exceeded the normal lifespan of the animals. An interesting hypothesis, then, is that SIV has adapted to induce a persistent infection that does not cause AIDS within the normal lifespan of natural host monkeys, and that AIDS may occur in those relatively rare monkeys that live longer than their expected lifespan and were infected at young age [140].
Table 3. Immunological Features of Natural SIV Infection of Sooty Mangabeys
· Normal or slightly decreased CD4+ T cell count
· Low levels of T cell activation during the acute and chronic phases of infection
· Preserved T cell regenerative capacity, with normal lymph node architecture, thymic and bone marrow function.
· Low levels of spontaneous and activation induced T cell apoptosis
· Inverse correlation between CD4+ T cell count and prevailing level of immune activation
· Limited SIV-specific T cell responses
6. Why is AIDS so rare in natural hosts for SIV infection?
HIV-infection of humans causes AIDS in the vast majority of cases, while natural SIV infection is most often completely asymptomatic. As discussed above, the level of viral replication does not explain this difference in outcome, which most likely is due to more complex mechanisms that involve both host and viral factors. We will now discuss five hypotheses (see Table 4) that we and others have put forward to explain the rarity of disease progression in natural hosts for SIV infection. We wish to emphasize that these hypotheses are not mutually exclusive, and that we discuss them separately for the sake of clarity only.
Table 4: Potential Mechanisms of Disease Resistance in the Natural Hosts of SIV (non mutually exclusive)
1. Increased lifespan on infected cells
2. Reduced number of available target cells
3. Limited immune activation and bystander apoptosis
4. More efficient T cell regeneration and redistribution
5. Effective immune control (unlikely, as the level of viral replication is usually high)
6.1 Are the SIV-specific immune responses more effective in natural hosts?
The discovery that natural hosts for SIV infection do not develop AIDS led to the somewhat obvious hypothesis that these animals avoid disease because they are able to exert better immune control of the virus. There is a major and still unresolved theoretical problem with this hypothesis, i.e., that an effective SIV-specific immune response would be predicted to result in lower levels of virus replication than those observed in pathogenic HIV/SIV infections. Instead, all performed studies have consistently shown that naturally SIV-infected monkeys have levels of plasma viremia as high or even higher than those observed in HIV-infected humans [15-20]. One potential explanation is that, although high viremia in SIVsmm-infected SMs clearly indicates incomplete immune control, it is still possible that the level of virus replication could be even higher in the absence of cellular immune responses. Partial control of virus replication via the immune response may be critical, then, in avoiding disease progression. As mentioned above, an extensive study performed in SIVsmm-infected SMs showed that the magnitude of the SIV-specific cellular immune responses is limited when compared to that observed in HIV-infected humans and does not correlate with plasma viremia or CD4+ T cell counts [161, 178]. In addition, depletion of CD8+ T cells from naturally SIV-infected SMs did not result in major changes of viral replication (Mark Feinberg, unpublished observations). Although similar studies have not been performed in other natural hosts, based on the data obtained in SMs, it may be concluded that SIV-specific cellular immune responses are not likely to be a key determinant of the absence of disease progresson in natural hosts for SIV infection.
6.2 Is SIV intrinsically less cytopathic in vivo in natural hosts?
The lack of disease progression in natural hosts for SIV infection may be explained by reduced virus cytopathicity, or, to be more accurate, by a longer average lifespan of infected cells in vivo. If infection of CD4+ T cells from natural hosts is followed by a greater duration, as compared to HIV-infected humans, of virus production, a high level of viremia could be conceivably reached in the presence of a relatively low fraction of infected CD4+ T cells. If fewer CD4+ T cells are killed at any given time, it would be easier for the immune system to replace them and thus to avoid any progressive CD4+ T cell depletion. According to this hypothesis, in naturally SIV-infected monkeys that develop progressive CD4+ T cell loss and AIDS, the intrinsic in vivo cytopathicity of the virus would be higher and the resultant accelerated killing of infected cells would ultimately compromise the homeostasis of the CD4+ T cell pool.
In HIV-infected patients that were treated with potent antiretroviral therapy (ART), the in vivo lifespan of cells infected with HIV has been inferred by the kinetics of decline of viral load following ART [179-181]. These studies concluded that the bulk of HIV replication occurs in recently infected cells that die soon after infection, likely as a result of a direct cytopathic effect of the virus (however, it should be noted that HIV preferentially infects activated CD4+ T cells that may be primed to die of activation-induced cell death regardless of their infection status). A similar approach could be used to assess the average lifespan of infected cells in SIV-infected natural hosts, and these studies are currently being performed in our laboratories in both SMs and AGMs. The hypothesis that in natural hosts for SIV infection the lifespan of infected cells is longer than in pathogenic HIV/SIV infections would predict that naturally SIV-infected animals manifest a slower decline of viremia post-ART. This potential prolonged lifespan of infected cells would contribute to the maintenance of high CD4+ T cell counts in natural hosts, with the exception of the animals with low CD4+ T cell counts that may show a slope of viremia decline similar to that described in HIV-infected patients. As mentioned, these studies are in progress ion our laboratory and we are now eagerly anticipating the results.
6.3 Are CD4+ T cells of natural hosts less susceptible to infection? (i.e., does the virus target a more limited subset of these cells?)
Pathogenic HIV/SIV infections are associated with early and persistent depletion of memory/activated CD4+CCR5+ T cells from the mucosal associated lymphoid tissues (MALT) [111, 182-185]. In these pathogenic infections, the virus co-receptor usage is a key factor in determining which CD4+ T cell subsets are depleted and from which anatomic sites, with an observed depletion of naïve CD4+ T cells from blood and lymph nodes by CXCR4-tropic viruses and depletion of memory CD4+ T cells in the blood and MALT by CCR5-tropic viruses [183, 186]. As CCR5 has been shown to be the main co-receptor used by SIV in natural hosts [187], it could be hypothesized that these animals, unlike non-natural hosts, avoid CD4+ T cell depletion from the mucosal tissues because their memory CD4+ T cells are less susceptible to SIV infection due to reduced CCR5 expression. In fact, natural hosts for SIV infection, and in particular SMs and AGMs, both SIV-infected and uninfected, do show decreased CCR5 expression on their memory CD4+ T cells, but not CD8+ T cells, in both peripheral blood and mucosal tissues, as compared to non-natural hosts such as macaques, baboons, and humans [155, 188, 189] . These results suggest that natural hosts have fewer CD4+ T cells that are susceptible to SIV infection then non-natural hosts, in which HIV/SIV infection is followed by progression to AIDS. In this perspective, the expression of CCR5 on a smaller fraction of memory/activated CD4+ T cells likely favors the preservation of the memory CD4+ T cell pool, especially in mucosal tissues, even if the virus infects and kills the majority of CD4+CCR5+ T cells. This hypothesis would be strongly supported by data indicating that memory CD4+ T cells are not depleted and/or are less extensively infected in the MALT during acute SIV-infection of natural hosts. In naturally SIV-infected monkeys with disease progression, a chronic loss of CD4+ T cells may be related to either an increased fraction of memory CD4+ T cells that express CCR5 or the presence of virus with expanded co-receptor usage. Both of these scenarios would induce CD4+ T cell depletion as the virus would now be capable of infecting and killing a larger fraction of memory CD4+ T cells. This hypothesis would provide an elegant evolutionary mechanism of "pacific co-existence" between SIV replication and natural host immune system function: with CCR5 expression restricted to a small subset of memory CD4+ T cells that are able to sustain the chronic high viremia in the majority of SMs, only this subset would be lost due to the direct cytopathic effect of SIV, but even a progressive depletion of this subset would not induce a major disruption of the memory CD4+ T cell homeostasis.
It should be noted, however, that to incorporate the unquestionable finding that SIV replicates to high levels in natural hosts, this hypothesis would predict either that the bulk of the measured SIV replication takes place in long-lived non-T cells (i.e., tissue macrophages), or that the infected CD4+ T cell produce a significantly higher amount of virus per individual infected cell (i.e., they have an increased lifespan). Interestingly, combined immunohistochemical analysis of SIV replication and phenotypic staining for T cells and macrophages in chronically SIVsmm-infected SMs and black mangabeys show that a greater number of macrophages than T cells is SIV-infected in the intestinal mucosa, suggesting that a significant proportion of productively SIV-infected cells in African non-human primates may be long-lived [177, 190]. More studies of the in vivo dynamics of SIVagm and SIVsmm replication are still needed to confirm that the major target cells of these viruses differ from those of SIVmac and HIV.
6.4 Are natural hosts for SIV infection protected from disease progression by lower levels of immune activation and bystander apoptosis?
A number of recent studies performed in SMs, AGMs, and mandrills indicate that both acute and chronic SIV infection of natural hosts is associated with lower levels of T cell activation, pro-inflammatory responses, immunopathology, and bystander apoptosis than pathogenic HIV/SIV infection [16, 18, 149, 150, 191]. Taken together, these results strongly support the hypothesis that an important (although not exclusive) mechanism favoring the preservation of CD4+ T cell homeostasis in natural hosts is the absence of generalized immune activation. In fact, the observation that SIV infection of natural hosts is associated with low levels of immune activation and apoptosis is in sharp contrast with the state of chronic generalized immune activation seen in HIV-infected individuals that is thought to contribute to the AIDS-associated T cell depletion [156, 158, 159, 192-195] and to predict disease progression [157, 196-200]. The well-demonstrated low level of immune activation in naturally SIV-infected monkeys may thus be a key factor in their lack of disease progression despite chronic high levels of viral replication. In this perspective, the observation of low SIV-specific cellular immune responses in SIVsmm-infected SMs can also be interpreted as a mechanism protecting naturally SIVsmm-infected SMs from the establishment of a state of chronic generalized immune activation. This hypothesis would predict that in the few animals that do lose CD4+ T cells (and may ultimately progress to AIDS) the level of immune activation is higher than in animals with higher CD4+ T cell counts. Studies are currently ongoing to test this hypothesis in several models of SIV infection of natural hosts. Ultimately, as low levels of immune activation may also be a consequence, rather than a cause, of a lack of pathogenicity due to other factors, we hope to more directly determine whether artificial enhancement of immune activation results in disease progression in natural hosts for SIV infection.
6.5 Is SIV infection of natural hosts associated with normal or even increased CD4+ T cell regeneration?
The possibility that a preserved or perhaps even enhanced T cell regenerative capacity plays a key role in determining the lack of disease progression in naturally SIV-infected monkeys is intriguing as, in HIV infection, a failure of the lymphoid regenerative capacity has been proposed to be an important factor in the pathogenesis of the immunodeficiency [156]. In particular, bone marrow suppression, reduced thymic output and loss of naive T cells have all been observed in HIV-infected individuals [201-207]. In marked contrast with this picture, our previous studies in SIV-infected SMs showed that the regenerative capacity of the CD4+ T cell compartment is fully preserved [18]. Two recent observations illustrate the critical role for interleukin-7 (IL-7)-dependent preserved T cell regeneration in avoiding CD4+ T cell depletion and disease progression in SIV-infected SMs. First, the timely triggering of an IL-7-dependent homeostatic mechanism is involved in maintaining high CD4+ T cell levels in experimentally SIVsmm-infected SMs [208]. Second, a direct correlation was found in SIVsmm-infected SMs between plasma levels of IL-7 and CD4+ T cell counts [209]. The hypothesis of a preserved lymphocyte regenerative compartment during non-pathogenic SIV infection of natural hosts is of interest as it may reflect an evolutionary adaptation of natural hosts whereby the chronic infection and killing of CD4+ T cells mediated by SIV is more effectively compensated by the production of new CD4+ T cells.
Concluding remarks and open questions.
We have reviewed the main epidemiological, virological, and immunological features of SIV infection of natural hosts, and find that the crucial but still unanswered question remains: why do SIV-infected natural hosts avoid AIDS while most HIV-infected humans do not? At this time, unfortunately, a simple and straightforward answer to this question is still missing. However, more pieces of the puzzle are fitting together. While the viral factor (i.e., reduced intrinsic cytopathicity and/or restricted tropism for CD4+ T cells) is far from being ruled out, it is fair to say that most of the available studies suggest that specific features of the host immune response play a key role in determining the specific phenotype of SIV infection in natural hosts. These features appear to be crucial not in terms of controlling viral replication per se (a task that is obviously not accomplished in natural SIV hosts), but instead by avoiding the generation of a state of chronic hyperactivation of the immune system that is ultimately more harmful than beneficial to the host. The molecular and cellular mechanisms responsible for the attenuated immune response observed in naturally SIV-infected monkeys in the face of a chronically high antigen load are currently under investigation and are likely to be complex. While additional evolutionary mechanisms may play an important role in avoiding disease progression in natural hosts (i.e., lower CCR5 expression, more effective CD4+ T cell regeneration) it is now clear that the co-evolution of SIV and its natural host monkey species has led to a state of disease-resistance that does not involve immunity to viral infection or viral replication, but rather reflects an evolutionary adaptation that allows for a pacific co-existence of host and virus. The importance of this observation, in our opinion, is in its implications for an understanding of the interactions between HIV and the human immune system. We feel strongly that further studies of the virology and immunology of natural SIV infections are needed to improve our understanding of the pathogenesis of HIV infection in humans. It is our hope that these conceptual advances will eventually translate into substantial improvements in the clinical management of HIV-infected patients.
Acknowledgments
The authors wish to thank Drs. Aftab Ansari, Daniel Douek, Jerome Estaquier, Mark Feinberg, Eric Hunter, Paul Johnson, Amitinder Kaur, Michael Lederman, Preston Marx, Harold McClure, Michaela Muller-Trutwin, Richard Onanga, Shawn O'Neil, Alan Perelson, Louis Picker, Pierre Roques, Donald Sodora, Silvija Staprans, Ronald Veazey, and Francois Villinger for the helpful discussion of data and hypotheses, and Dr. Ann Chahroudi for critical reading of the manuscript. This work was supported by grants R01 AI-052775 and R21 AI-054234 (GS), P51- NIH-NCRR-RR00165 (Yerkes), P20 RR-020159 (CA), P51 RR-000164 (CA & IP), RO1 AI-064066 (IP), all from the National Institutes of Health. This manuscript is dedicated to the memory of our colleague and friend Dr. Harold McClure.
References
[1] Hahn, B. H., et al., AIDS as a zoonosis: scientific and public health implications. Science, 2000. 287(5453): p. 607-14.
[2] Gao, F., et al., Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes. Nature, 1999. 397(6718): p. 436-41.
[3] Peeters, M., et al., Isolation and partial characterization of an HIV-related virus occurring naturally in chimpanzees in Gabon. Aids, 1989. 3(10): p. 625-30.
[4] Gao, F., et al., Human infection by genetically diverse SIVSM-related HIV-2 in west Africa. Nature, 1992. 358(6386): p. 495-9.
[5] Marx, P. A., et al., Isolation of a simian immunodeficiency virus related to human immunodeficiency virus type 2 from a west African pet sooty mangabey. J. Virol., 1991. 65(8): p. 4480-5.
[6] Hirsch, V. M., et al., An African primate lentivirus (SIVsm) closely related to HIV-2. Nature, 1989. 339(6223): p. 389-92.
[7] Murphey-Corb, M., et al., Isolation of an HTLV-III-related retrovirus from macaques with simian AIDS and its possible origin in asymptomatic mangabeys. Nature, 1986. 321(6068): p. 435-7.
[8] Daniel, M. D., et al., Isolation of T-cell tropic HTLV-III-like retrovirus from macaques. Science, 1985. 228(4704): p. 1201-4.
[9] Johnson, P. R. and V. M. Hirsch, SIV infection of macaques as a model for AIDS pathogenesis. Int Rev Immunol, 1992. 8(1): p. 55-63.
[10] Fultz, P. N., et al., Prevalence of natural infection with simian immunodeficiency virus and simian T-cell leukemia virus type I in a breeding colony of sooty mangabey monkeys. AIDS, 1990. 4(7): p. 619-25.
[11] Bailes, E., et al., The evolution of primate lentiviruses and origins of AIDS, in The molecular epidemiology of human viruses, T. A. Leitner, Editor. 2002, Kluwer Academic Publishers: Boston, Mass. p. p. 65-96.
[12] Souquiere, S., et al., Wild Mandrillus sphinx are carriers of two types of lentivirus. J. Virol., 2001. 75(15): p. 7086-96.
[13] Takehisa, J., et al., Natural infection of wild-born mandrills (Mandrillus sphinx) with two different types of simian immunodeficiency virus. AIDS Res. Hum. Retroviruses, 2001. 17(12): p. 1143-54.
[14] Cichutek, K. and S. Norley, Lack of immune suppression in SIV-infected natural hosts. Aids, 1993. 7 Suppl 1: p. S25-35.
[15] Rey-Cuille, M. A., et al., Simian immunodeficiency virus replicates to high levels in sooty mangabeys without inducing disease. J. Virol., 1998. 72(5): p. 3872-86.
[16] Chakrabarti, L. A., et al., Normal T-cell turnover in sooty mangabeys harboring active simian immunodeficiency virus infection. J. Virol., 2000. 74(3): p. 1209-23.
[17] Broussard, S. R., et al., Simian immunodeficiency virus replicates to high levels in naturally infected African green monkeys without inducing immunologic or neurologic disease. J. Virol., 2001. 75(5): p. 2262-75.
[18] Silvestri, G., et al., Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia. Nature, 2003. 18(3): p. 441-52.
[19] Holzammer, S., et al., High virus loads in naturally and experimentally SIVagm-infected African green monkeys. Nature, 2001. 283(2): p. 324-31.
[20] Pandrea, I., et al., High levels of SIVmnd-1 replication in chronically infected Mandrillus sphinx. Nature, 2003. 317(1): p. 119-27.
[21] Hirsch, H. H., et al., Immune reconstitution in HIV-infected patients. Clin Infect Dis, 2004. 38(8): p. 1159-66.
[22] Mellors, J. W., et al., Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science, 1996. 272(5265): p. 1167-70.
[23] Mellors, J. W., et al., Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med, 1997. 126(12): p. 946-54.
[24] Allan, J. S., et al., Species-specific diversity among simian immunodeficiency viruses from African green monkeys. J. Virol., 1991. 65(6): p. 2816-28.
[25] Staprans, S. I., et al., Simian immunodeficiency virus disease course is predicted by the extent of virus replication during primary infection. J. Virol., 1999. 73(6): p. 4829-39.
[26] Stevenson, M., HIV-1 pathogenesis. Nat Med, 2003. 9(7): p. 853-60.
[27] Stebbing, J., B. Gazzard, and D. C. Douek, Where does HIV live? N. Engl. J. Med., 2004. 350(18): p. 1872-80.
[28] Groves, C., Primate taxonomy. Smithsonian Institution Press., 2001. Washington & London.
[29] Harris, E. E. and T. R. Disotell, Nuclear gene trees and the phylogenetic relationship of the mangabeys (Primates: Papionini). Mol. Biol. Evol., 1998. 15(7): p. 892-900.
[30] Tosi, A. J., D. J. Melnick, and T. R. Disotell, Sex chromosome phylogenetics indicate a single transition to terrestriality in the guenons (tribe Cercopithecini). J. Hum. Evol., 2004. 46(2): p. 223-37.
[31] Beer, B. E., et al., Diversity and evolution of primate lentiviruses. in: Human Retroviruses and AIDS 1999. Edited by: Kuiken CL, Foley B, Hahn B, Korber B, McCutchan F, Marx PA, Mellors JW, Mullins JI, Sodroski J, and Wolinksy S., 1999. Published by: Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM: p. 460-474.
[32] Sharp, P. M., et al., Origins and evolution of AIDS viruses: estimating the time-scale. Biochem. Soc. Trans., 2000. 28(2): p. 275-82.
[33] Lowenstine, L. J., et al., Seroepidemiologic survey of captive Old-World primates for antibodies to human and simian retroviruses, and isolation of a lentivirus from sooty mangabeys (Cercocebus atys). Int. J. Cancer., 1986. 38(4): p. 563-74.
[34] Ohta, Y., et al., Isolation of simian immunodeficiency virus from African green monkeys and seroepidemiologic survey of the virus in various non-human primates. Int. J. Cancer., 1988. 41(1): p. 115-22.
[35] Hendry, R. M., et al., Antibodies to simian immunodeficiency virus in African green monkeys in Africa in 1957-62. Lancet, 1986. 2(8504): p. 455.
[36] Muller, M. C., et al., Simian immunodeficiency viruses from central and western Africa: evidence for a new species-specific lentivirus in tantalus monkeys. J. Virol., 1993. 67(3): p. 1227-35.
[37] Diop, O. M., et al., Simian immunodeficiency viruses and the origin of HIVs. 2nd Edition ed. AIDS in Africa, ed. M. Essex, et al. 2002: Kluwer Academic/Plenum Publishers. 104-120.
[38] Phillips-Conroy, J. E., et al., Sexual transmission of SIVagm in wild grivet monkeys. J. Med. Primatol., 1994. 23(1): p. 1-7.
[39] Denham, W. W., History of Green Monkeys in the West Indies: Part I. Migration from Africa. Journal of B. M. H. S., 1981. 36: p. 210-229.
[40] Chen, Z., et al., Genetic characterization of new West African simian immunodeficiency virus SIVsm: geographic clustering of household-derived SIV strains with human immunodeficiency virus type 2 subtypes and genetically diverse viruses from a single feral sooty mangabey troop. J. Virol., 1996. 70(6): p. 3617-27.
[41] Apetrei, C., et al., Detection and partial characterization of new simian immunodeficiency virus (SIVsm) strains from bush meat samples from rural Sierra Leone. J. Virol., 2005. 79(4): p. 2631-2636.
[42] Santiago, M. L., et al., Endemic SIVsm infection in wild-living sooty mangabeys. 11th Conference on Retroviruses and Opportunistic Infections, 2004. San Francisco, CA(February): Abstr. 380.
[43] Simon, F., et al., Synthetic peptide strategy for the detection of and discrimination among highly divergent primate lentiviruses. AIDS Res. Hum. Retroviruses, 2001. 17(10): p. 937-52.
[44] Georges-Courbot, M. C., et al., Natural infection of a household pet red-capped mangabey (Cercocebus torquatus torquatus) with a new simian immunodeficiency virus. J. Virol., 1998. 72(1): p. 600-8.
[45] Beer, B. E., et al., Patterns of genomic sequence diversity among their simian immunodeficiency viruses suggest that L'Hoest monkeys (Cercopithecus lhoesti) are a natural lentivirus reservoir. J. Virol., 2000. 74(8): p. 3892-8.
[46] Emau, P., et al., Isolation from African Sykes' monkeys (Cercopithecus mitis) of a lentivirus related to human and simian immunodeficiency viruses. J. Virol., 1991. 65(4): p. 2135-40.
[47] Hirsch, V. M., et al., A distinct African lentivirus from Sykes' monkeys. J. Virol., 1993. 67(3): p. 1517-28.
[48] Tomonaga, K., et al., Isolation and characterization of simian immunodeficiency virus from African white-crowned mangabey monkeys (Cercocebus torquatus lunulatus). J. Virol., 1993. 129(1-4): p. 77-92.
[49] Hahn, B., Bernard Fields Memorial Lecture: SIV reservoirs and human zoonotic risk. 9th Conference on Retroviruses and Opportunistic Infections., 2002. Seattle WA: p. Abstr. # L1.
[50] Courgnaud, V., et al., Partial molecular characterization of two simian immunodeficiency viruses (SIV) from African colobids: SIVwrc from Western red colobus (Piliocolobus badius) and SIVolc from olive colobus (Procolobus verus). J. Virol., 2003. 77(1): p. 744-8.
[51] Courgnaud, V., et al., Characterization of a novel simian immunodeficiency virus from guereza colobus monkeys (Colobus guereza) in Cameroon: a new lineage in the nonhuman primate lentivirus family. J. Virol., 2001. 75(2): p. 857-66.
[52] Apetrei, C., D. L. Robertson, and P. A. Marx, The history of SIVS and AIDS: epidemiology, phylogeny and biology of isolates from naturally SIV infected non-human primates (NHP) in Africa. Front Biosci, 2004. 9: p. 225-54.
[53] Peeters, M., et al., Isolation and characterization of a new chimpanzee lentivirus (simian immunodeficiency virus isolate cpz-ant) from a wild-captured chimpanzee. Aids, 1992. 6(5): p. 447-51.
[54] Santiago, M. L., et al., Foci of endemic simian immunodeficiency virus infection in wild-living eastern chimpanzees (Pan troglodytes schweinfurthii). J. Virol., 2003. 77(13): p. 7545-62.
[55] Santiago, M. L., et al., Amplification of a complete simian immunodeficiency virus genome from fecal RNA of a wild chimpanzee. J. Virol., 2003. 77(3): p. 2233-42.
[56] Santiago, M. L., et al., SIVcpz in wild chimpanzees. Science, 2002. 295(5554): p. 465.
[57] Corbet, S., et al., env sequences of simian immunodeficiency viruses from chimpanzees in Cameroon are strongly related to those of human immunodeficiency virus group N from the same geographic area. J. Virol., 2000. 74(1): p. 529-34.
[58] Nerrienet, E., et al., Simian immunodeficiency virus infection in wild-caught chimpanzees from cameroon. J. Virol., 2005. 79(2): p. 1312-9.
[59] Sharp, P. M., G. M. Shaw, and B. H. Hahn, Simian immunodeficiency virus infection of chimpanzees. J. Virol., 2005. 79(7): p. 3891-902.
[60] Prince, A. M., et al., Lack of evidence for HIV type 1-related SIVcpz infection in captive and wild chimpanzees (Pan troglodytes verus) in West Africa. AIDS Res. Hum. Retroviruses, 2002. 18(9): p. 657-60.
[61] Van Dooren, S., et al., Lack of evidence for infection with simian immunodeficiency virus in bonobos. AIDS Res. Hum. Retroviruses, 2002. 18(3): p. 213-6.
[62] Georges-Courbot, M. C., et al., Occurrence and frequency of transmission of naturally occurring simian retroviral infections (SIV, STLV, and SRV) at the CIRMF Primate Center, Gabon. J. Med. Primatol., 1996. 25(5): p. 313-26.
[63] Estaquier, J., et al., Prevalence and transmission of simian immunodeficiency virus and simian T-cell leukemia virus in a semi-free-range breeding colony of mandrills in Gabon. Aids, 1991. 5(11): p. 1385-6.
[64] Cooper, R., et al., A lack of evidence of sexual transmission of a simian immunodeficiency agent in a semifree-ranging group of mandrills. AIDS, 1989. 3: p. 764.
[65] Nerrienet, E., et al., Phylogenetic analysis of SIV and STLV type I in mandrills (Mandrillus sphinx): indications that intracolony transmissions are predominantly the result of male-to-male aggressive contacts. AIDS Res. Hum. Retroviruses, 1998. 14(9): p. 785-96.
[66] Lowenstine, L. J., et al., Evidence for a lentiviral etiology in an epizootic of immune deficiency and lymphoma in stump-tailed macaques (Macaca arctoides). J. Med. Primatol., 1992. 21(1): p. 1-14.
[67] Otsyula, M. G., et al., Apparent lack of vertical transmission of simian immunodeficiency virus (SIV) in naturally infected African green monkeys, Cercopithecus aethiops. Ann Trop Med Parasitol, 1995. 89(5): p. 573-6.
[68] Peeters, M., et al., Risk to human health from a plethora of simian immunodeficiency viruses in primate bushmeat. Emerg. Infect. Dis., 2002. 8(5): p. 451-7.
[69] Pandrea, I., et al. Lack of breast-feeding transmission during SIVmnd-1 primary infection in Mandrillus sphinx. in XIV-th International Conference on AIDS. 2002. Barcelona, Spain.
[70] Apetrei, C. and P. A. Marx, Simian retroviral infections in human beings. Lancet, 2004. 364(9429): p. 137-8.
[71] Marx, P. A., P. G. Alcabes, and E. Drucker, Serial human passage of simian immunodeficiency virus by unsterile injections and the emergence of epidemic human immunodeficiency virus in Africa. Philos Trans R Soc Lond B Biol Sci, 2001. 356(1410): p. 911-20.
[72] Drucker, E., P. G. Alcabes, and P. A. Marx, The injection century: massive unsterile injections and the emergence of human pathogens. Lancet, 2001. 358(9297): p. 1989-92.
[73] Jin, M. J., et al., Mosaic genome structure of simian immunodeficiency virus from west African green monkeys. EMBO J, 1994. 13(12): p. 2935-47.
[74] Bailes, E., et al., Hybrid origin of SIV in chimpanzees. Science, 2003. 300(5626): p. 1713.
[75] Hu, J., et al., Characterization and comparison of recombinant simian immunodeficiency virus from drill (Mandrillus leucophaeus) and mandrill (Mandrillus sphinx) isolates. J. Virol., 2003. 77(8): p. 4867-80.
[76] Courgnaud, V., et al., Identification of a new simian immunodeficiency virus lineage with a vpu gene present among different cercopithecus monkeys (C. mona, C. cephus, and C. nictitans) from Cameroon. J. Virol., 2003. 77(23): p. 12523-34.
[77] Bibollet-Ruche, F., et al., Simian immunodeficiency virus infection in a patas monkey (Erythrocebus patas): evidence for cross-species transmission from African green monkeys (Cercopithecus aethiops sabaeus) in the wild. J. Gen. Virol., 1996. 77: p. 773-81.
[78] Jin, M. J., et al., Infection of a yellow baboon with simian immunodeficiency virus from African green monkeys: evidence for cross-species transmission in the wild. J. Virol., 1994. 68(12): p. 8454-60.
[79] van Rensburg, E. J., et al., Simian immunodeficiency viruses (SIVs) from eastern and southern Africa: detection of a SIVagm variant from a chacma baboon. J. Gen. Virol., 1998. 79: p. 1809-14.
[80] Hirsch, V. M., et al., Induction of AIDS by simian immunodeficiency virus from an African green monkey: species-specific variation in pathogenicity correlates with the extent of in vivo replication. J. Virol., 1995. 69(2): p. 955-67.
[81] Smith, S. M., et al., SIVrcm infection of macaques. J. Med. Primatol., 1998. 27(2-3): p. 94-8.
[82] Johnson, P. R., et al., Molecular clones of SIVsm and SIVagm: experimental infection of macaques and African green monkeys. J. Med. Primatol., 1990. 19(3-4): p. 279-86.
[83] Kaiser, S. M. and M. Emerman, Controlling lentiviruses: single amino acid changes can determine specificity. Proc. Natl. Acad. Sci. U S A, 2004. 101(11): p. 3725-6.
[84] Zhang, H., et al., The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA. Nature, 2003. 424(6944): p. 94-8.
[85] Harris, R. S., et al., DNA deamination mediates innate immunity to retroviral infection. Cell, 2003. 113(6): p. 803-9.
[86] Mangeat, B., et al., Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts. Nature, 2003. 424(6944): p. 99-103.
[87] Lecossier, D., et al., Hypermutation of HIV-1 DNA in the absence of the Vif protein. Science, 2003. 300(5622): p. 1112.
[88] Simon, J. H. and M. H. Malim, The human immunodeficiency virus type 1 Vif protein modulates the postpenetration stability of viral nucleoprotein complexes. J. Virol., 1996. 70(8): p. 5297-305.
[89] Schrofelbauer, B., D. Chen, and N. R. Landau, A single amino acid of APOBEC3G controls its species-specific interaction with virion infectivity factor (Vif). Proc. Natl. Acad. Sci. U S A, 2004. 101(11): p. 3927-32.
[90] Bogerd, H. P., et al., A single amino acid difference in the host APOBEC3G protein controls the primate species specificity of HIV type 1 virion infectivity factor. Proc. Natl. Acad. Sci. U S A, 2004. 101(11): p. 3770-4.
[91] Xu, H., et al., A single amino acid substitution in human APOBEC3G antiretroviral enzyme confers resistance to HIV-1 virion infectivity factor-induced depletion. Proc. Natl. Acad. Sci. U S A, 2004. 101(15): p. 5652-7.
[92] Goff, S. P., HIV: replication trimmed back. Nature, 2004. 427(6977): p. 791-3.
[93] Stremlau, M., et al., The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys. Nature, 2004. 427(6977): p. 848-53.
[94] Miller, R. J., et al., Human immunodeficiency virus and AIDS: insights from animal lentiviruses. J. Virol., 2000. 74(16): p. 7187-95.
[95] VandeWoude, S., et al., Nonpathogenic lion and puma lentiviruses impart resistance to superinfection by virulent feline immunodeficiency virus. J Acquir Immune Defic Syndr, 2002. 29(1): p. 1-10.
[96] Hirsch, V. M., et al., Characterization of a novel simian immunodeficiency virus (SIV) from L'Hoest monkeys (Cercopithecus l'hoesti): implications for the origins of SIVmnd and other primate lentiviruses. J. Virol., 1999. 73(2): p. 1036-45.
[97] Tsujimoto, H., et al., Sequence of a novel simian immunodeficiency virus from a wild-caught African mandrill. Nature, 1989. 341(6242): p. 539-41.
[98] Verschoor, E. J., et al., A novel simian immunodeficiency virus isolated from a Schmidt's guenon (Cercopithecus ascanius schmidti). J. Gen. Virol., 2004. 85(Pt 1): p. 21-4.
[99] Bibollet-Ruche, F., et al., A new simian immunodeficiency virus lineage (SIVdeb) infecting de Brazza's monkeys (Cercopithecus neglectus): Evidence for a Cercopithecus monkey virus clade. J. Virol., 2004. 78(14): p. 7748-7762.
[100] Huet, T., et al., Genetic organization of a chimpanzee lentivirus related to HIV-1. Nature, 1990. 345(6273): p. 356-9.
[101] Wain-Hobson, S., M. Alizon, and L. Montagnier, Relationship of AIDS to other retroviruses. Nature, 1985. 313(6005): p. 743.
[102] Beer, B. E., et al., Characterization of novel simian immunodeficiency viruses from red-capped mangabeys from Nigeria (SIVrcmNG409 and -NG411). J. Virol., 2001. 75(24): p. 12014-27.
[103] Guyader, M., et al., Genome organization and transactivation of the human immunodeficiency virus type 2. Nature, 1987. 326(6114): p. 662-9.
[104] Chakrabarti, L., et al., Sequence of simian immunodeficiency virus from macaque and its relationship to other human and simian retroviruses. Nature, 1987. 328(6130): p. 543-7.
[105] Simon, J. H., et al., The regulation of primate immunodeficiency virus infectivity by Vif is cell species restricted: a role for Vif in determining virus host range and cross-species transmission. EMBO J, 1998. 17(5): p. 1259-67.
[106] Osterhaus, A. D., et al., Isolation and partial characterization of a lentivirus from talapoin monkeys (Myopithecus talapoin). Nature, 1999. 260(1): p. 116-24.
[107] Nerrienet, E., et al. New primate lentivirus from agile monkey (Cercocebus agilis) suggests a host-dependent evolution within mangabeys in Central Africa. in XIV-th International Conference on AIDS. 2002. Barcelona, Spain.
[108] Sharp, P. M., et al., Origins and evolution of AIDS viruses. Biol Bull, 1999. 196(3): p. 338-42.
[109] Salemi, M., et al., Mosaic genomes of the six major primate lentivirus lineages revealed by phylogenetic analyses. J. Virol., 2003. 77(13): p. 7202-13.
[110] Chakrabarti, L. A., A. Luckay, and P. A. Marx, A divergent simian immunodeficiency virus from sooty mangabey with an atypical Tat-TAR structure. AIDS Res. Hum. Retroviruses, 2001. 17(12): p. 1155-65.
[111] Ling, B., et al., Noninvasive detection of new simian immunodeficiency virus lineages in captive sooty mangabeys: ability to amplify virion RNA from fecal samples correlates with viral load in plasma. J. Virol., 2003. 77(3): p. 2214-26.
[112] Peeters, M., et al., Isolation of simian immunodeficiency viruses from two sooty mangabeys in Cote d'Ivoire: virological and genetic characterization and relationship to other HIV type 2 and SIVsm/mac strains. AIDS Res. Hum. Retroviruses, 1994. 10(10): p. 1289-94.
[113] Fultz, P. N., et al., Isolation of a T-lymphotropic retrovirus from naturally infected sooty mangabey monkeys (Cercocebus atys). Proc. Natl. Acad. Sci. U S A, 1986. 83(14): p. 5286-90.
[114] Gao, F., et al., Genetic diversity of human immunodeficiency virus type 2: evidence for distinct sequence subtypes with differences in virus biology. J. Virol., 1994. 68(11): p. 7433-47.
[115] Damond, F., et al., Identification of a highly divergent HIV-2 and proposal for a change in HIV-2 classification. AIDS Res. Hum. Retroviruses, 2004. 20: p. 666-672.
[116] Gardner, M. B., The history of simian AIDS. J. Med. Primatol., 1996. 25(3): p. 148-57.
[117] Mansfield, K. G., et al., Origins of simian immunodeficiency virus infection in macaques at the New England Regional Primate Research Center. J. Med. Primatol., 1995. 24(3): p. 116-22.
[118] Apetrei, C., et al., Molecular epidemiology of SIVsm in US Primate Centers unravels the origin of SIVmac and SIVstm. J. Virol., 2005. 79: p. in press.
[119] Daniel, M. D., et al., Simian immunodeficiency virus from African green monkeys. J. Virol., 1988. 62(11): p. 4123-8.
[120] Hirsch, V. M., et al., Identification of a new subgroup of SIVagm in tantalus monkeys. Nature, 1993. 197(1): p. 426-30.
[121] Fukasawa, M., et al., Sequence of simian immunodeficiency virus from African green monkey, a new member of the HIV/SIV group. Nature, 1988. 333(6172): p. 457-61.
[122] Baier, M., et al., Complete nucleotide sequence of a simian immunodeficiency virus from African green monkeys: a novel type of intragroup divergence. Nature, 1990. 176(1): p. 216-21.
[123] Fomsgaard, A., et al., A highly divergent proviral DNA clone of SIV from a distinct species of African green monkey. Nature, 1991. 182(1): p. 397-402.
[124] Hirsch, V. M. and P. R. Johnson, Pathogenic diversity of simian immunodeficiency viruses. Virus Res, 1994. 32(2): p. 183-203.
[125] Johnson, P. R., et al., Simian immunodeficiency viruses from African green monkeys display unusual genetic diversity. J. Virol., 1990. 64(3): p. 1086-92.
[126] Beer, B. E., et al., Simian immunodeficiency virus (SIV) from sun-tailed monkeys (Cercopithecus solatus): evidence for host-dependent evolution of SIV within the C. lhoesti superspecies. J. Virol., 1999. 73(9): p. 7734-44.
[127] Santiago, M. L., et al., Noninvasive detection of Simian immunodeficiency virus infection in a wild-living L'Hoest's monkey (Cercopithecus Ihoesti). AIDS Res. Hum. Retroviruses, 2003. 19(12): p. 1163-6.
[128] Tsujimoto, H., et al., Isolation and characterization of simian immunodeficiency virus from mandrills in Africa and its relationship to other human and simian immunodeficiency viruses. J. Virol., 1988. 62(11): p. 4044-50.
[129] Vanden Haesevelde, M. M., et al., Sequence analysis of a highly divergent HIV-1-related lentivirus isolated from a wild captured chimpanzee. Nature, 1996. 221(2): p. 346-50.
[130] Janssens, W., et al., Phylogenetic analysis of a new chimpanzee lentivirus SIVcpz-gab2 from a wild-captured chimpanzee from Gabon. AIDS Res. Hum. Retroviruses, 1994. 10(9): p. 1191-2.
[131] Worobey, M., et al., Origin of AIDS: contaminated polio vaccine theory refuted. Nature, 2004. 428(6985): p. 820.
[132] Apetrei, C., Unpublished Observations. 2005, Tulane Regional Primate Research Center, Tulane University, New Orleans, LA, USA.
[133] Moore, J. P., et al., The CCR5 and CXCR4 coreceptorscentral to understanding the transmission and pathogenesis of human immunodeficiency virus type 1 infection. AIDS Res. Hum. Retroviruses, 2004. 20(1): p. 111-26.
[134] Zhang, Y., et al., Use of inhibitors to evaluate coreceptor usage by simian and simian/human immunodeficiency viruses and human immunodeficiency virus type 2 in primary cells. J. Virol., 2000. 74(15): p. 6893-910.
[135] Chen, Z., et al., Genetically divergent strains of simian immunodeficiency virus use CCR5 as a coreceptor for entry. J. Virol., 1997. 71(4): p. 2705-14.
[136] Schols, D. and E. De Clercq, The simian immunodeficiency virus mnd(GB-1) strain uses CXCR4, not CCR5, as coreceptor for entry in human cells. J. Gen. Virol., 1998. 79 (Pt 9): p. 2203-5.
[137] Owen, S. M., et al., Simian immunodeficiency viruses of diverse origin can use CXCR4 as a coreceptor for entry into human cells. J. Virol., 2000. 74(12): p. 5702-8.
[138] Pandrea, I., et al., Impact of viral factors on very early in vivo replication profiles in SIVagm-infected African green monkeys. J. Virol., 2005. 79: p. in press.
[139] Ling, B., et al., Classic AIDS in a sooty mangabey after an 18-year natural infection. J. Virol., 2004. 78(16): p. 8902-8.
[140] Pandrea, I., et al., Chronic SIV infection ultimately causes immunodeficiency in African non-human primates. AIDS, 2001. 15(18): p. 2461-2.
[141] Chen, Z., et al., Natural infection of a homozygous delta24 CCR5 red-capped mangabey with an R2b-tropic simian immunodeficiency virus. J Exp Med, 1998. 188(11): p. 2057-65.
[142] Lyles, R. H., et al., Natural history of human immunodeficiency virus type 1 viremia after seroconversion and proximal to AIDS in a large cohort of homosexual men. Multicenter AIDS Cohort Study. J Infect Dis, 2000. 181(3): p. 872-80.
[143] Mellors, J. W., Viral-load tests provide valuable answers. Sci Am, 1998. 279(1): p. 90-3.
[144] Chakrabarti, L. A., et al., Age-dependent changes in T cell homeostasis and SIV load in sooty mangabeys. J. Med. Primatol., 2000. 29(3-4): p. 158-65.
[145] Diop, O. M., et al., High levels of viral replication during primary simian immunodeficiency virus SIVagm infection are rapidly and strongly controlled in African green monkeys. J. Virol., 2000. 74(16): p. 7538-47.
[146] Onanga, R., et al., High levels of viral replication contrast with only transient changes in CD4+ and CD8+ cell numbers during the early phase of experimental infection with simian immunodeficiency virus SIVmnd-1 in Mandrillus sphinx. J. Virol., 2002. 76(20): p. 10256-63.
[147] Onanga, R., et al., Extensive viral load during SIVmnd-2 infection in Mandrillus sphinx is associated with lack with transitory immune activation of CD4+ T cells and expansion of CD8+ T cells in lymph nodes. 2005: p. submitted.
[148] Estaquier, J., et al., Programmed cell death and AIDS: significance of T-cell apoptosis in pathogenic and nonpathogenic primate lentiviral infections. Proc. Natl. Acad. Sci. U S A, 1994. 91(20): p. 9431-5.
[149] Kornfeld, C., et al., Antiinflammatory profiles during primary SIV infection in African green monkeys are associated with protection against AIDS. J Clin Invest, 2005. 115(4): p. 1082-1091.
[150] Silvestri, G., et al., Divergent host responses during primary simian immunodeficiency virus SIVsm infection of natural sooty mangabey and nonnatural rhesus macaque hosts. J. Virol., 2005. 79(7): p. 4043-54.
[151] Villinger, F., et al., Comparative sequence analysis of cytokine genes from human and nonhuman primates. J Immunol, 1995. 155(8): p. 3946-54.
[152] Kaur, A., et al., Identification of multiple simian immunodeficiency virus (SIV)-specific CTL epitopes in sooty mangabeys with natural and experimentally acquired SIV infection. J Immunol, 2000. 164(2): p. 934-43.
[153] Kaur, A., et al., Emergence of cytotoxic T lymphocyte escape mutations in nonpathogenic simian immunodeficiency virus infection. Eur J Immunol, 2001. 31(11): p. 3207-17.
[154] Bostik, P., et al., Relative resistance in the development of T cell anergy in CD4+ T cells from simian immunodeficiency virus disease-resistant sooty mangabeys. J Immunol, 2001. 166(1): p. 506-16.
[155] Veazey, R., et al., Decreased CCR5 expression on CD4+ T cells of SIV-infected sooty mangabeys. AIDS Res. Hum. Retroviruses, 2003. 19(3): p. 227-33.
[156] McCune, J. M., The dynamics of CD4+ T-cell depletion in HIV disease. Nature, 2001. 410(6831): p. 974-9.
[157] Hazenberg, M. D., et al., Persistent immune activation in HIV-1 infection is associated with progression to AIDS. Aids, 2003. 17(13): p. 1881-8.
[158] Grossman, Z., et al., CD4+ T-cell depletion in HIV infection: are we closer to understanding the cause? Nat Med, 2002. 8(4): p. 319-23.
[159] Silvestri, G. and M. B. Feinberg, Turnover of lymphocytes and conceptual paradigms in HIV infection. J Clin Invest, 2003. 112(6): p. 821-4.
[160] Sumpter, B., Unpublished observations. 2005, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.
[161] Dunham, R., Unpublished observations. 2005, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.
[162] Gordon, S., Unpublished observations. 2005, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.
[163] Milush, J., et al. AIDS-defining CD4+ T-cell Levels in the Absence of Clinical Syptoms Induced by SIVsmm Inoculation of Sooty Mangabeys. in Conference on Retroviruses and Opportunistic Infections. 2005. Boston, Mass., USA.
[164] Goulder, P. J. and D. I. Watkins, HIV and SIV CTL escape: implications for vaccine design. Nat Rev Immunol, 2004. 4(8): p. 630-40.
[165] Betts, M. R., et al., Analysis of total human immunodeficiency virus (HIV)-specific CD4(+) and CD8(+) T-cell responses: relationship to viral load in untreated HIV infection. J. Virol., 2001. 75(24): p. 11983-91.
[166] Novembre, F. J., et al., Development of AIDS in a chimpanzee infected with human immunodeficiency virus type 1. J. Virol., 1997. 71(5): p. 4086-91.
[167] Peeters, M., et al., Virologic and serologic characteristics of a natural chimpanzee lentivirus infection. Nature, 1995. 211(1): p. 312-5.
[168] Kestens, L., et al., Phenotypic and functional parameters of cellular immunity in a chimpanzee with a naturally acquired simian immunodeficiency virus infection. J Infect Dis, 1995. 172(4): p. 957-63.
[169] O'Neil, S. P., et al., Progressive infection in a subset of HIV-1-positive chimpanzees. J Infect Dis, 2000. 182(4): p. 1051-62.
[170] Heeney, J., et al., Immune strategies utilized by lentivirus infected chimpanzees to resist progression to AIDS. Immunol Lett, 1996. 51(1-2): p. 45-52.
[171] Gougeon, M. L., et al., Comparative analysis of apoptosis in HIV-infected humans and chimpanzees: relation with lymphocyte activation. Immunol Lett, 1996. 51(1-2): p. 75-81.
[172] Koopman, G., et al., The relative resistance of HIV type 1-infected chimpanzees to AIDS correlates with the maintenance of follicular architecture and the absence of infiltration by CD8+ cytotoxic T lymphocytes. AIDS Res. Hum. Retroviruses, 1999. 15(4): p. 365-73.
[173] McClure, H. M., et al., Natural simian immunodeficiency virus infection in nonhuman primates. Top. Primatol., 1992. 3: p. 425-438.
[174] Traina-Dorge, V., et al., Immunodeficiency and lymphoproliferative disease in an African green monkey dually infected with SIV and STLV-I. AIDS Res. Hum. Retroviruses, 1992. 8(1): p. 97-100.
[175] Barnett, S. W., et al., An AIDS-like condition induced in baboons by HIV-2. Science, 1994. 266(5185): p. 642-6.
[176] Novembre, F. J., et al., Rapid CD4(+) T-cell loss induced by human immunodeficiency virus type 1(NC) in uninfected and previously infected chimpanzees. J. Virol., 2001. 75(3): p. 1533-9.
[177] Apetrei, C., et al., Direct inoculation of simian immunodeficiency virus from sooty mangabeys in black mangabeys (Lophocebus aterrimus): first evidence of AIDS in a heterologous African species and different pathologic outcomes of experimental infection. J. Virol., 2004. 78(21): p. 11506-18.
[178] Wang, Z., et al. Relationship between Cellular Immune Responses and Viral Load in Naturally SIV-infected Sooty Mangabeys. in Conference on Retroviruses and Opportunistic Infections. 2005. Boston, Mass., USA.
[179] Wei, X., et al., Viral dynamics in human immunodeficiency virus type 1 infection. Nature, 1995. 373(6510): p. 117-22.
[180] Ho, D. D., et al., Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature, 1995. 373(6510): p. 123-6.
[181] Perelson, A. S., et al., HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science, 1996. 271(5255): p. 1582-6.
[182] Veazey, R. S., et al., Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science, 1998. 280(5362): p. 427-31.
[183] Picker, L. J., et al., Insufficient production and tissue delivery of CD4+ memory T cells in rapidly progressive simian immunodeficiency virus infection. J Exp Med, 2004. 200(10): p. 1299-314.
[184] Brenchley, J. M., et al., CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med, 2004. 200(6): p. 749-59.
[185] Mehandru, S., et al., Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J Exp Med, 2004. 200(6): p. 761-70.
[186] Harouse, J. M., et al., Distinct pathogenic sequela in rhesus macaques infected with CCR5 or CXCR4 utilizing SHIVs. Science, 1999. 284(5415): p. 816-9.
[187] Chen, Z., et al., Primary SIVsm isolates use the CCR5 coreceptor from sooty mangabeys naturally infected in west Africa: a comparison of coreceptor usage of primary SIVsm, HIV-2, and SIVmac. Nature, 1998. 246(1): p. 113-24.
[188] Pandrea, I., et al. Lack of SIV target cells in African non-human primate: host or virus adaptation? in 11th Conference on Retroviruses and Opportunistic Infections. 2004. San Francisco, CA, USA.
[189] Pandrea, I., et al. Decreased CCR5 Expression on CD4+ T Cells of African Green Monkeys (AGMs). in 21st Annual Symposium on Nonhuman Primate Models for AIDS. 2003. Seattle, WA.
[190] Pandrea, I., Unpublished Observations. 2005, Tulane Regional Primate Research Center, Tulane University, New Orleans, LA, USA.
[191] Muller-Trutwin, M. C., et al., The evolutionary rate of nonpathogenic simian immunodeficiency virus (SIVagm) is in agreement with a rapid and continuous replication in vivo. Nature, 1996. 223(1): p. 89-102.
[192] Chun, T. W., et al., Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature, 1997. 387(6629): p. 183-8.
[193] Anderson, R. W., M. S. Ascher, and H. W. Sheppard, Direct HIV cytopathicity cannot account for CD4 decline in AIDS in the presence of homeostasis: a worst-case dynamic analysis. J Acquir Immune Defic Syndr Hum Retrovirol, 1998. 17(3): p. 245-52.
[194] Haase, A. T., Population biology of HIV-1 infection: viral and CD4+ T cell demographics and dynamics in lymphatic tissues. Annu Rev Immunol, 1999. 17: p. 625-56.
[195] Hazenberg, M. D., et al., T cell depletion in HIV-1 infection: how CD4+ T cells go out of stock. Nat Immunol, 2000. 1(4): p. 285-9.
[196] Leng, Q., et al., Immune activation correlates better than HIV plasma viral load with CD4 T-cell decline during HIV infection. J Acquir Immune Defic Syndr, 2001. 27(4): p. 389-97.
[197] Sousa, A. E., et al., CD4 T cell depletion is linked directly to immune activation in the pathogenesis of HIV-1 and HIV-2 but only indirectly to the viral load. J Immunol, 2002. 169(6): p. 3400-6.
[198] Giorgi, J. V., et al., Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect Dis, 1999. 179(4): p. 859-70.
[199] Liu, Z., et al., Elevated CD38 antigen expression on CD8+ T cells is a stronger marker for the risk of chronic HIV disease progression to AIDS and death in the Multicenter AIDS Cohort Study than CD4+ cell count, soluble immune activation markers, or combinations of HLA-DR and CD38 expression. J Acquir Immune Defic Syndr Hum Retrovirol, 1997. 16(2): p. 83-92.
[200] Giorgi, J. V., et al., Predictive value of immunologic and virologic markers after long or short duration of HIV-1 infection. J Acquir Immune Defic Syndr, 2002. 29(4): p. 346-55.
[201] Roederer, M., et al., CD8 naive T cell counts decrease progressively in HIV-infected adults. J Clin Invest, 1995. 95(5): p. 2061-6.
[202] Marandin, A., et al., Loss of primitive hematopoietic progenitors in patients with human immunodeficiency virus infection. Blood, 1996. 88(12): p. 4568-78.
[203] Moses, A., J. Nelson, and G. C. Bagby, Jr., The influence of human immunodeficiency virus-1 on hematopoiesis. Blood, 1998. 91(5): p. 1479-95.
[204] Douek, D. C., et al., Changes in thymic function with age and during the treatment of HIV infection. Nature, 1998. 396(6712): p. 690-5.
[205] Douek, D. C., et al., Evidence for increased T cell turnover and decreased thymic output in HIV infection. J Immunol, 2001. 167(11): p. 6663-8.
[206] Hellerstein, M., et al., Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans. Nat Med, 1999. 5(1): p. 83-9.
[207] Ullum, H., et al., Increased losses of CD4+CD45RA+ cells in late stages of HIV infection is related to increased risk of death: evidence from a cohort of 347 HIV-infected individuals. Aids, 1997. 11(12): p. 1479-85.
[208] Muthukumar, A., Manuscript in revision. Blood, 2005.
[209] Paiardini, M., Unpublished observations. 2005, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.
[210] Dazza, M. C., et al., Characterization of novel simian immunodeficiency virus from Cercopithecus mona denti (SIVden) from the Democratic Republic of Congo. J Virol: in press.
[211] Takemura, T., et al., A novel simian immunodeficiency virus from black mangabey (Lophocebus aterrimus) in the Democratic Republic of Congo. J. Gen. Virol., 2005, 86:1967-71.
[212] Courgnaud, V., et al., Full molecular characterization of simian immunodeficiency virus infecting talapoins monkeys: Evidence for a new SIV lineage in Miopithecus species. 11th Conference on Retroviruses and Opportunistic Infections San Francisco, CA, 2004: Abstr. 379.
[213] Reed, P., et al., Presented at the 2nd IAS Conference on HIV pathogenesis and threatment, Paris, France, 2003.
Copyright © 2005-2006 LANSLLC All rights reserved | Disclaimer/Privacy | SITE MAP
