Human immunodeficiency virus type 1 (HIV-1), the cause of human acquired immunodeficiency syndrome (AIDS), is a zoonotic infection of staggering proportions and social impact. Yet uncertainty persists regarding its natural reservoir. The virus most closely related to HIV-1 is a simian immunodeficiency virus (SIV) thus far identified only in captive members of the chimpanzee subspecies Pan troglodytes troglodytes. Here we report the detection of SIVcpz antibodies and nucleic acids in fecal samples from wild-living P. t. troglodytes apes in southern Cameroon, where prevalence rates in some communities reached 29 to 35%. By sequence analysis of endemic SIVcpz strains, we could trace the origins of pandemic (group M) and nonpandemic (group N) HIV-1 to distinct, geographically isolated chimpanzee communities. These findings establish P. t. troglodytes as a natural reservoir of HIV-1.

High-level immune activation and T cell apoptosis represent a hallmark of HIV-1 infection that is absent from nonpathogenic SIV infections in natural primate hosts. The mechanisms causing these varying levels of immune activation are not understood. Here, we report that nef alleles from the great majority of primate lentiviruses, including HIV-2, downmodulate TCR-CD3 from infected T cells, thereby blocking their responsiveness to activation. In contrast, nef alleles from HIV-1 and a subset of closely related SIVs fail to downregulate TCR-CD3 and to inhibit cell death. Thus, Nef-mediated suppression of T cell activation is a fundamental property of primate lentiviruses that likely evolved to maintain viral persistence in the context of an intact host immune system. This function was lost during viral evolution in a lineage that gave rise to HIV-1 and may have predisposed the simian precursor of HIV-1 for greater pathogenicity in humans.

Summary The mechanism by which CD4 T-cells are depleted in HIV-infected hosts remains poorly understood. In ex vivo cultures of human tonsil tissue, CD4 T cells undergo a pronounced cytopathic response following HIV infection. Strikingly, >95% of these dying cells are not productively infected but instead correspond to bystander cells. We now show that the death of these “bystander” cells involves abortive HIV infection. Inhibitors blocking HIV entry or early steps of reverse transcription prevent CD4 T-cell death while inhibition of later events in viral life cycle does not. We propose that the nonpermissive state exhibited by the majority of resting CD4 tonsil T-cells leads to accumulation of incomplete reverse transcripts. These cytoplasmic nucleic acids activate a host defense program that elicits a coordinated proapoptotic and proinflammatory response involving caspase-3 and caspase-1 activation. While this response likely evolved to protect the host, it centrally contributes to the immunopathogenic effects of HIV.

RNA granules ͉ Ro ribonucleoproteins ͉ prespliceosomes T he intrinsic antiretroviral factor APOBEC3G (A3G) is highly active against HIV-1 and other retroviruses (1). Incorporation of A3G into budding HIV-1 virions promotes extensive mutation of nascent HIV-1 DNA formed by reverse transcription in the next round of infection (2-5). However, HIV-1 counters these effects of A3G with virion infectivity factor (Vif), which accelerates proteasome-mediated degradation of A3G (6-11) and partially impairs de novo synthesis of A3G (6, 12). These two actions in virus-producing cells effectively deplete intracellular A3G, making the enzyme unavailable for virion encapsidation. Resting CD4 T cells and monocytes, which are refractory to HIV-1 infection, express only the low-molecular-mass (LMM) form of A3G (13). siRNAmediated knockdown of LMM A3G expression in resting CD4 T cells renders these cells permissive for HIV-1 infection, indicating that LMM A3G functions as a potent postentry restriction factor for HIV-1 (13). Conversely, resting CD4 T cells in lymphoid tissues are permissive for HIV-1 infection, and A3G is predominantly in high-molecular-mass (HMM) complexes in these cells (14) because of the lymphoid microenvironment. Locally produced cytokines, including IL-2 and IL-15, and cell-cell interactions in lymphoid tissues stimulate assembly of the HMM A3G complexes (14) and confer permissiveness for HIV-1 infection.The genes encoding A3G and other APOBEC3 (A3) family members are clustered on human chromosome 22 (15). During mammalian evolution, this locus expanded from a single gene in mice to eight genes (A3A-H) in primates (15, 16). These genes apparently have been modulated by repeated episodes of strong Abbreviations: HMM, high-molecular-mass; LMM, low-molecular-mass; RNP, ribonucleoprotein; A3G, APOBEC3G; L1, long interspersed nucleotide elements 1; TAP, tandem affinity purification; IP, immunoprecipitation; co-IP, coimmunoprecipitation; scAlu, small cytoplasmic Alu; PB, processing body. ¶ To whom correspondence should be addressed. E-mail: wgreene@gladstone.ucsf.

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