Toward an AIDS vaccine: lessons from natural simian immunodeficiency virus infections of African nonhuman primate hosts.

Seattle Biomedical Research Institute, Seattle, Washington, USA.
Nature medicine (Impact Factor: 28.05). 09/2009; 15(8):861-5. DOI: 10.1038/nm.2013
Source: PubMed

ABSTRACT The design of an effective AIDS vaccine has eluded the efforts of the scientific community to the point that alternative approaches to classic vaccine formulations have to be considered. We propose here that HIV vaccine research could greatly benefit from the study of natural simian immunodeficiency virus (SIV) infections of African nonhuman primates. Natural SIV hosts (for example, sooty mangabeys, African green monkeys and mandrills) share many features of HIV infection of humans; however, they usually do not develop immunodeficiency. These natural, nonprogressive SIV infections represent an evolutionary adaptation that allows a peaceful coexistence of primate lentiviruses and the host immune system. This adaptation does not result in reduced viral replication but, rather, involves phenotypic changes to CD4(+) T cell subsets, limited immune activation and preserved mucosal immunity, all of which contribute to the avoidance of disease progression and, possibly, to the reduction of vertical SIV transmission. Here we summarize the current understanding of SIV infection of African nonhuman primates and discuss how unraveling these evolutionary adaptations may provide clues for new vaccine designs that might induce effective immune responses without the harmful consequences of excessive immune activation.

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    ABSTRACT: Background African non-human primates are SIV natural hosts and do not develop disease following infection. Understanding disease avoidance mechanisms in these species is important for HIV vaccine development. The largest captive population of sooty mangabeys, a SIV natural host species, resides at the Yerkes National Primate Research Center.Methods Thirteen primer sets that amplify polymorphic microsatellite loci within the MHC region were used to genotype 144 animals. Immunogenetic Management Software (IMS) was used to identify MHC haplotypes and organize data.ResultsSeventy-three haplotypes were identified. Limited haplotype diversity was observed in this population with 88.2% of included animals carrying one of 18 haplotypes. Differences in haplotype frequency were observed between SIV (+) and SIV (−) populations.Conclusions We have developed a novel tool for others to use in the analysis of the role of the MHC in a natural host non-human primate model species used for SIV research.
    Journal of Medical Primatology 01/2015; DOI:10.1111/jmp.12161 · 0.89 Impact Factor
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    ABSTRACT: The role of the accessory viral Nef protein as a multi-functional manipulator of the host cell that is required for effective replication of HIV and SIV in vivo is well established. It is unknown, however, whether Nef manipulates all or just specific subsets of CD4+ T cells that are the main targets of virus infection and differ substantially in their state of activation and importance for a functional immune system. Here, we analyzed the effect of Nef proteins differing in their TCR-CD3 downmodulation function in HIV infected human lymphoid aggregate cultures and peripheral blood mononuclear cells. We found that Nef efficiently downmodulates TCR-CD3 in naïve and memory CD4+ T cells and protects the latter against apoptosis. In contrast, highly proliferative CD45RA+CD45RO+CD4+ T cells were main producers of infectious virus but largely refractory to TCR-CD3 downmodulation. Such T cell subset-specific differences were also observed for Nef-mediated modulation of CD4 but not for enhancement of virion infectivity. Our results indicate that Nef predominantly modulates surface receptors on CD4+ T cell subsets that are not already fully permissive for viral replication. As a consequence, Nef-mediated downmodulation of TCR-CD3 that distinguishes most primate lentiviruses from HIV-1 and its vpu containing simian precursors may promote a selective preservation of central memory CD4+ T cells that are critical for the maintenance of a functional immune system. The Nef proteins of human and simian immunodeficiency viruses manipulate infected CD4+ T cells in multiple ways to promote viral replication and immune evasion in vivo. Here, we show that some effects of Nef are subset-specific. Downmodulation of CD4 and TCR-CD3 is highly effective in central memory CD4+ T cells and the latter Nef function protects this T cell subset against apoptosis. In contrast, highly activated/proliferating CD4+ T cells are largely refractory to receptor downmodulation but main producers of infectious HIV-1. Nef-mediated enhancement of virion infectivity, however, was observed in all T cell subsets examined. Our results provide new insights into how primate lentiviruses manipulate their target cells and suggest that the TCR-CD3 downmodulation function of Nef may promote a selective preservation of memory CD4+ T cells that are critical for immune function but has little effect on activated/proliferating CD4+T cells that are main targets for viral replication. Copyright © 2014, American Society for Microbiology. All Rights Reserved.
    Journal of Virology 12/2014; DOI:10.1128/JVI.03104-14 · 4.65 Impact Factor
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    ABSTRACT: 14 15 Word count abstract = 250 16 Word count importance = 141 17 Word count text = 3798 18 19 JVI Accepts, published online ahead of print on 29 October 2014 J. Virol.
    Journal of Virology 10/2014; DOI:10.1128/JVI.02430-14 · 4.65 Impact Factor

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