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Natural SIV infection of sooty mangabeys (SMs) is nonprogressive despite chronic virus replication. Strikingly, it is characterized by low levels of immune activation, while pathogenic SIV infection of rhesus macaques (RMs) is associated with chronic immune activation. To elucidate the mechanisms underlying this intriguing phenotype, we used high-density oligonucleotide microarrays to longitudinally assess host gene expression in SIV-infected SMs and RMs. We found that acute SIV infection of SMs was consistently associated with a robust innate immune response, including widespread upregulation of IFN-stimulated genes (ISGs) in blood and lymph nodes. While SMs exhibited a rapid resolution of ISG expression and immune activation, both responses were observed chronically in RMs. Systems biology analysis indicated that expression of the lymphocyte inhibitory receptor LAG3, a marker of T cell exhaustion, correlated with immune activation in SIV-infected RMs but not SMs. Our findings suggest that active immune regulatory mechanisms, rather than intrinsically attenuated innate immune responses, underlie the low levels of immune activation characteristic of SMs chronically infected with SIV., Introduction HIV infection is characterized by progressive depletion of [CD4.sup.+] T cells that eventually results in clinically significant immunodeficiency. Although development of AIDS occurs years after primary HIV infection, it [...]

Naturally SIV-infected sooty mangabeys (SMs) remain asymptomatic despite high virus replication. Elucidating the mechanisms underlying AIDS resistance of SIV-infected SMs may provide crucial information to better understand AIDS pathogenesis. In this study, we assessed the determinants of set-point viremia in naturally SIV-infected SMs, i.e., immune control of SIV replication versus target cell limitation. We depleted [CD4.sup.+] T cells in 6 naturally SIV-infected SMs by treating with humanized anti-CD4 mAb (Cdr-OKT4A-huIgG1). [CD4.sup.+] T cells were depleted almost completely in blood and BM and at variable levels in mucosal tissues and LNs. No marked depletion of [CD14.sup.+] monocytes was observed. Importantly, [CD4.sup.+] T cell depletion was associated with a rapid, significant decline in viral load, which returned to baseline level at day 30-45, coincident with an increased fraction of proliferating and activated [CD4.sup.+] T cells. Throughout the study, virus replication correlated with the level of proliferating [CD4.sup.+] T cells. [CD4.sup.+] T cell depletion did not induce any changes in the fraction of Tregs or the level of SIV-specific [CD8.sup.+] T cells. Our results suggest that the availability of activated [CD4.sup.+] T cells, rather than immune control of SIV replication, is the main determinant of set-point viral load during natural SIV infection of SMs., Introduction The HIV epidemic in humans arose after zoonotic transmission of simian [CD4.sup.+] T cell tropic lentiviruses, which naturally infect a range of African monkey host species and are now [...]