Type I interferon induction and elimination of memory T cells by HIV and other primate lentiviruses

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Aberrant immune activation and increased apoptosis drive progression to AIDS. Interestingly, these characteristic features of HIV-1 infection are absent in non-human primates that are naturally infected with SIV and do not develop disease despite high viral loads. The reasons for these different clinical outcomes of HIV-1 and SIV infection remain poorly understood. We hypothesize that some features that are characteristic of HIV-1, such as the presence of a vpu gene, the lack of TCR-CD3 down-modulation by Nef, and frequent usage of the coreceptor CXCR4 may render this virus particularly virulent. Our preliminary data support that HIV-1 induces higher levels of type I interferons (IFN) than HIV-2 or SIV and that a functional vpu gene contributes to this effect. Furthermore, we found that Nef-mediated down-modulation of TCR-CD3 specifically protects CD4+ memory T cells against programmed death. Here, we want to further define these effects. Type I IFN is mainly induced by CD4-mediated virion uptake by plasmacytoid dendritic cells (pDCs) and subsequent triggering of Toll-like receptors (TLRs). Thus, HIV-1 may induce particularly high levels of type I IFN because Vpu-mediated antagonism of tetherin and CD4 degradation increases virion release and binding of HIV-1 to CD4. Through comparative analyzes of HIV-1 with "non-pathogenic" SIV clones, we will determine the relevance of HIV-1-specific features for inflammatory cytokine induction. Furthermore, we will determine whether most primate lentiviruses may coexist in a benign relationship with their natural primate hosts because their Nef proteins protect T cell subsets that are critical for immune function against programmed death. Finally, it is currently poorly understood which circulating factors in the human body modulate HIV-induced inflammation and apoptosis. Thus, we will screen blood-derived peptide-protein libraries to identify circulating factors modulating these processes. Our long-term vision is to further optimize such natural modulators of inflammatory responses and HIV-dependent apoptosis to prevent the damaging chronic immune activation in treated and untreated HIV-infected individuals.