Role of Nef-mediated TCR-CD3 downmodulation in the pathogenesis of AIDS

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Recently, we have shown that the inability of Nef to downmodulate TCR-CD3 may explain why high-level immune activation and AIDS represent a hallmark of HIV-1 infection but is absent from asymptomatic natural SIV infections. We also found that nef alleles from naturally SIVsmm-infected sooty mangabeys preserving their CD4+ T-cell counts exhibit significantly higher activity in TCR-CD3 downmodulation than those derived from the minor percentage of animals with low CD4+ T-cell numbers. These data suggest that the ability of Nef to downmodulate TCR-CD3 may allow the natural simian hosts of SIV to remain immunocompetent and healthy despite high levels of viral replication. However, direct evidence fora protective role of TCR-CD3 downmodulation in vivo is missing. Therefore, we want to compare the pathogenicity and immunological properties of SIVagm variants differing specifically in the ability of Nef to modulate TCR-CD3 in infected African Green Monkeys. The results of this study will clarify whether inhibition of T-cell activation by CDS downregulation protects against AIDS and help to assess whether treatments preventing hyperactivation of the immune response in infected humans - mimicking the tight balance maintained in the other primates - may offer new prospects for antiretroviral therapy.