TRIM5α Neutralizes Mammalian Retroviruses TRIM5α has indeed been confirmed to be an essential component of the Ref1 restrictive activity observed in human cell lines (Fig. 1) (3–6). Expression of human TRIM5α in otherwise permissive cells is sufficient to confer resistance to N-MLV but not B-MLV infection. Significantly, human cells transfected with small interfering RNA (siRNA) targeting endogenous TRIM5α causes these cells to be nearly as sensitive to N-MLV infection as they are to B-MLV infection. Functional characterization of AGM and rhesus TRIM5α variants recapitulates a broad restriction to N-MLV with no effect on B-MLV infection. Beyond N-MLV restriction, the different TRIM5α variants recognize lentiviruses parasitic to other species. Although AGM TRIM5α is ineffective against SIV isolated from AGM, its expression is sufficient to restrict HIV-1 or an SIV isolate propagated in macaques (4). Consistent with these data, TRIM5α-specific siRNA treatment of AGM cells enhances their sensitivity to HIV-1 infection (5). Considered with results first observed using rhesus cells (7), it would appear that TRIM5α from Old World primates accounts for Lv1. Finally, although human TRIM5α is less effective at deterring infection by primate lentiviruses, human, rhesus, or AGM TRIM5α can diminish infection by equine infectious anemia virus, a nonprimate lentivirus (4, 5). | Fig. 1.Antiviral fusillade. Fv1, TRIM1, or TRIM5α restriction of N-MLV (blue), B-MLV (green), SIVmac. (lavender), or HIV-1 (red). Boxes indicate species-specific restrictive measures targeting invading retroviral particles. h, Human; rh, rhesus macaque; (more ...) |
Notably, the HIV-1 restrictive activity present in New World primates, such as owl monkeys, has yet to be identified. HIV-1 restriction in owl monkey kidney (OMK) cells can be pharmacologically manipulated through treatment with the immunosuppressant cyclosporine A (CsA), a competitive inhibitor of host cell cyclophilin A (CypA). CsA-treated OMK cells are 100-fold more permissive to HIV-1 infection than untreated cells are (22). Because HIV-1 capsid is known to interact with CypA (23), it has been postulated that this interaction in OMK cells may contribute to HIV-1 restriction. Understanding the relationship between CypA and HIV-1 restrictions in these cells will require a description of owl monkey TRIM5. In contrast, the HIV-1 restrictive properties of cells from Old World primates are significantly less affected by CsA treatment. Consistent with this observation, two reports (3, 6) indicate that HIV-1 capsid mutated to prevent CypA binding is still sensitive to AGM and rhesus macaque TRIM5α. Although a link between CypA and TRIM5α remains to be uncovered, an exciting interaction between Fv1-N and TRIM5α was detected by using human cell transfectants (5). Human TE671 cells restrict N-MLV infection by virtue of their endogenously expressed TRIM5α (3, 5). These cells can be made resistant to B-MLV infection through the stable expression of Fv1-N, creating so-called TEN cells (18). Strikingly, when TEN cells are treated with siRNA to “knock down” endogenous TRIM5α, Fv1-N restriction of B-MLV is lost (5). These data hint at a dependence of Fv1 antiviral function on a TRIM-family protein from mouse. Given the common specificity of Fv1-B and human TRIM5α for N-MLV capsid residue 110, such a relationship is not altogether surprising. Although there is no TRIM5 present in mice, there are a number of orthologs. Investigating potential interactions between murine TRIM-family proteins with N- and B-tropic MLV will likely provide insight toward the elusive mechanism of Fv1 restriction. Findings by Yap et al. (3) provide optimism in screening other TRIM family proteins for antiretroviral properties. TRIM1 isolated from humans and nonhuman primates moderately restricts N-MLV infection. Sensitivity to TRIM1 restriction mapped to the same MLV capsid determinants that specify reactivity to TRIM5α or Fv1 proteins. Defining shared TRIM1 and TRIM5α regions required for antiviral function may help identify other restrictive factors from the TRIM family. |
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