Vanessa M. Hirsch. D.V.M., D.Sc.

Senior Investigator

Dr. Hirsch received her D.V.M. from the University of Saskatchewan in Canada in 1977, and did a residency in pathology at the University of Saskatchewan, becoming board certified by the American College of Veterinary Pathologists in 1984. She earned her D.Sc. degree from Harvard School of Public Health, Boston, MA, in 1988. She was a research assistant professor at Georgetown University until 1992, when she joined the NIAID Laboratory of Infectious Diseases, transferring to the Laboratory of Molecular Microbiology (LMM) in 1999.

Description of Research Program

My group uses simian immunodeficiency virus infection of monkeys as a model to study the pathogenesis of human AIDS and to develop effective vaccine strategies.

SIV is a highly relevant animal model for AIDS because it induces an immunodeficiency syndrome in macaque monkeys that is remarkably similar to that seen in HIV-infected humans. Although HIV-1 infection of humans is a fatal disease, the disease course is highly variable, ranging from asymptomatic survival for over 15 years to rapid progression to AIDS within 2 years of infection. The level at which plasma viremia stabilizes following primary HIV infection is a highly significant prognostic indicator of subsequent disease course, suggesting that host immune mechanisms are critical in the control of viremia. Studies in my laboratory have shown that SIV-infected macaques also exhibit variable disease course and viral load is a strong predictor of disease progression. My laboratory investigates host and viral factors that contribute to the variable disease course in SIV infection of macaques.

Another avenue of my research is the investigation of the origins of primate lentiviruses, including HIV-1, by examining its close relatives in African monkeys. It is important to remember that SIV-infection of macaques, an Asian monkey, is an artificial experimental animal model. SIVs originate in primates of African origin, including sooty mangabeys (SIVsm), African green monkeys (SIVagm), Sykes' monkeys (SIVsyk), mandrills (SIVmnd), and red-capped mangabeys (SIVrcm). My lab has been responsible for characterizing a number of these strains of SIV, including SIVsm, SIVagm from three of the four species of African green monkeys, SIVs from two related African monkeys, L'Hoest monkey (SIVlhoest) and sun-tailed monkey (SIVsun), SIVsyk, SIVrcm, SIVmnd-2 and SIVdrl. A close genetic relationship between SIVagm strains and SIVlhoest and SIVsun, despite their long term (more than 10,000 years) geographic separation, provides support for the hypothesis that the primate lentiviruses have co-evolved within African monkeys over the last million years. However, our studies also demonstrated that cross-species transmission between primates has occurred and that some of strains are clearly recombinant.

Despite serologic evidence of widespread infection with SIV in many African monkeys, AIDS-like disease is observed only in macaques. SIVsm infection of sooty mangabey monkeys is asymptomatic, whereas inoculation of this same virus strain into macaques results in AIDS. My laboratory has demonstrated that SIVagm, SIVlhoest, and SIVsun, while apathogenic for their natural host species, induce AIDS in macaques. This discrepancy in the virulence of a common SIV strain for its natural host species and macaque monkeys provides a valuable model to study species-specificity of virulence and allows us the opportunity to examine the underlying mechanisms of attenuation in the natural host species. The study of the species-specific virulence of SIV infection in macaques versus AGM is a focus of my pathogenesis studies.

Equally important is the development of a vaccine for AIDS, and this is the other focus of my research. Although anti-retroviral therapy has had a significant impact on the survival of HIV-infected patients, treatment is costly and can lead to the emergence of drug-resistant viral mutants. Thus the development of safe, realistic, and effective vaccine strategies is essential. Unfortunately, many of the vaccine approaches tested thus far have resulted in only partial protection from infection in primate models of AIDS.

My laboratory has focused on developing a vaccine based on the use of live viral vectors to prime a cell-mediated immune response. I have concentrated these studies upon the use of a highly attenuated vaccinia virus, modified vaccinia virus Ankara (MVA) because we demonstrated that vaccination with MVA-expressing SIV genes resulted in significant modulation of viremia and improved survival when these animals were exposed to virus.

Selected Data

1. Vaccination with MVA recombinants of SIV induces good cellular immune responses and decreases viral load following pathogenic SIV challenge. MVA recombinants of SIV Gag-Pol, Env, and a combination of Gag-Pol and Env resulted in significant reduction in set point viremia following challenge with pathogenic SIVsmE660 and significantly prolonged survival. The strength of the peak, pre-challenge CTL response correlated inversely with the degree of viral suppression following challenge consistent with a significant role for CTL in mediating protection in this model (see Ourmanov, et al., 2000 and Seth, et al., 2000).
2. SIVagm (Hirsch, et al., 1995) and SIVlhoest (Hirsch, et al., 1999) induce AIDS when inoculated into pigtailed macaques although these viruses result in asymptomatic infection of their natural host. Both of these viruses result in high levels of virus replication in macaques and induce a slow progressive loss of CD4+ T cells in the blood and tissues.
3. African green monkeys naturally infected with SIVagm exhibit a wide range of viral loads from undetectable to close to a million copies, suggesting that containment of viremia does not explain the lack of disease in naturally-infected primates (see Goldstein, et al., 2000).
4. In an earlier vaccine study we demonstrated that the pattern of viral replication, specifically the plateau levels of viremia, was predictive of the rate of disease progression (see Hirsch, et al., 1999). To investigate this phenomenon further, we studied susceptibility of CD4+ T cells of various macaques to infection with SIV as a predictor of in vivo viral replication. Intrinsic susceptibility of peripheral blood CD4+ T cells to in vitro infection with SIV was found to be predictive of subsequent in vivo viremia (see Goldstein, et al., 2000 and Figure 1) suggesting that host factors play a major role in the rate of disease progression in SIV-infection of macaques.
   
   

   Figure 1: Panel A shows the variable extent of plasma viral RNA in a cohort of six rhesus macaques selected to include the full range of intrinsic susceptibility in vitro. As shown in panel B, the extent of viremia in these animals correlated significantly with the susceptibility of their peripheral blood lymphocytes to SIV infection in vitro (Goldstein, et al., 2000).

5. We have been studying the unique pathology and evolution of virus in rapid progressor macaques. Rapid progressor (RP) macaques progress to AIDS in less than 6 months from the time of inoculation and exhibit uncontrolled viral replication and failure of cellular and humoral immune responses. Studies of tissues of RP macaques at end stage reveal that the majority of SIV-infected cells are macrophages including multinucleated giant cells (see Figure 2). Virus in macaques that progress rapidly to AIDS evolves in unusual and conserved regions of envelope and is associated with evolution of CD4-independent use of CCR5 (see Dehghani, et al., 2003). The majority of sequence changes in rapid progressor macaques occurred in the envelope gene. Substitutions were observed in all three animals at specific conserved residues in envelope, including loss of a glycosylation site in V1/V2, a D to N/V substitution in a highly conserved GDPE motif, and a P to V/H/T substitution in the V3 loop analog. A cell-cell fusion assay revealed that representative env clones utilized CCR5 as a coreceptor, independent of CD4. The selection of specific substitutions in envelope in RP macaques suggests novel selection pressures on virus in such animals and suggests that viral variants that evolve in these animals may play a role in disease progression.
   
   

   Figure 2: Choroid plexus (brain) sample from an SIV infected rhesus macaque stained for SIV RNA (green) and macrophages (red). This double staining technique identifies the location and type of cells that are present in the SIV infected monkey.

6. Molecular characterization of SIV from red capped mangabeys (SIVrcm; Beer, et al., 2002), SIV from L'Hoest monkeys (SIVlhoest; Beer, et al., 2000), SIV from sun-tailed monkeys (SIVsun; Beer, et al. 1999), SIV from drills (SIVdrl; Hu, et al., 2003). These studies demonstrated phylogenetic clustering of SIVlhoest and SIVsun consistent with the close phylogenetic relationship of their host species and suggestive of co-evolution of SIV in African primates. SIVdrl and SIVmnd-2 were also phylogenetically related. Interestingly these viruses were both recombinants of a SIVrcm-like virus and SIVlhoest-like virus and share a common recombinant point suggesting a recent common evolutionary origin consistent with cross-species transmission. The phylogenetic relationship between these viruses is shown in Figure 3.
   
   

   Figure 3: Phylogenetic clustering of SIVlhoest and SIVsun.

Research Group Members

Front row from left:
Sonya Whitted - Technician, swhitted@niaid.nih.gov; Gia Tran, Student IRTA, ntran@niaid.nih.gov; Jayashree Nandi, Ph.D., Research Fellow, snandi@niaid.nih.gov; Vanessa Hirsch; Que Dang, Ph.D., Postdoctoral IRTA, qdang@niaid.nih.gov; Simoy Goldstein Ph.D., Senior Research Assistant, sgoldstein@niaid.nih.gov.
Back row from left:
Charles Brown, B.S., Biologist, crbrown@niaid.nih.gov; Takeo Takeo Kuwata, Ph.D., Visiting Fellow, tkuwata@niaid.nih.gov; Ilnour Ourmanov, Ph.D., Staff Scientist, iourmanov@niaid.nih.gov; Robert Goeken, M.S., Biologist, rgoeken@niaid.nih.gov; Charles Fischer.
Not pictured:
Rose Butler, Secretary, robutler@niaid.nih.gov.

Selected Publications

(View list in PubMed.)

Goldstein S, Ourmanov I, Brown CR, Plishka R, Buckler-White A, Byrum R, Hirsch VM. Plateau levels of viremia correlate with the degree of CD4+-T-cell loss in simian immunodeficiency virus SIVagm-infected pigtailed macaques: Variable pathogenicity of natural SIVagm isolates. J Virol. 2005. 79: 5153-5162.

Hirsch VM. What can natural infection of African monkeys with simian immunodeficiency virus tell us about the pathogenesis of AIDS? AIDS Rev. 2004. 6: 40-53.

Hirsch VM, Santra S, Goldstein S, Plishka R, Buckler-White A, Seth A, Ourmanov I, Brown CR, Engle R, Montefiori D, Glowczwskie J, Kunstman K, Wolinsky S, Letvin NL. Immune failure in the absence of profound CD4+ T-lymphocyte depletion in simian immunodeficiency virus-infected rapid progressor macaques. J Virol. 2004. 78: 275.

Dehghani H, Puffer BA, Doms RW, Hirsch VM. Unique pattern of convergent envelope evolution in simian immunodeficiency virus-infected rapid progressor macaques: association with CD4-independent usage of CCR5. J Virol. 2003. 77(11): 6405-6418.

Hu J, Switzer WM, Foley BT, Robertson DL, Goeken RM, Korber BT, Hirsch VM, Beer BE. Characterization and comparison of recombinant simian immunodeficiency virus from drill (Mandrillus leucophaeus) and mandrill (Mandrillus sphinx) isolates. J Virol. 2003. 77(8): 4867-4880.

Beer BE, Foley BT, Kuiken CL, Tooze Z, Goeken RM, Brown CR, Hu J, St Claire M, Korber BT, Hirsch VM. Characterization of novel simian immunodeficiency viruses from red-capped mangabeys from Nigeria (SIVrcmNG409 and -NG411). J Virol. 2001. 75(24): 12014-12027.

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