Virus (SIV) Infection of Natural Hosts from Pathogenic

The mechanisms underlying the AIDS resistance of natural hosts for simian immunodeficiency virus (SIV) remain unknown. Recently, it was proposed that natural SIV hosts avoid disease because their plasmacytoid dendritic cells (pDCs) are intrinsically unable to produce alpha interferon (IFN-) in response to SIV RNA stimulation. However, here we show that (i) acute SIV infections of natural hosts are associated with a rapid and robust type I IFN response in vivo, (ii) pDCs are the principal in vivo producers of IFN-/ at peak acute infection in lymphatic tissues, and (iii) natural SIV hosts downregulate these responses in early chronic infection. In contrast, persistently high type I IFN responses are observed during pathogenic SIV infection of rhesus macaques. A hallmark of pathogenic human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infections is per-sistent chronic activation of the immune system that is associ-ated with (i) dysfunctions in cellular and humoral immunity, (ii) elevated levels of activation-induced cell death in all lym-phocyte subsets, and (iii) failure to effectively control viru