African green monkeys (AGMs) infected with the AGM type of SIV (SIVagm) do not develop chronic immune activation and AIDS, despite viral loads similar to those detected in humans infected with HIV-1 and rhesus macaques (RMs) infected with the RM type of SIV (SIVmac). Because chronic immune activation drives progressive CD4 + T cell depletion and immune cell dysfunctions, factors that characterize disease progression, we sought to understand the molecular basis of this AGM phenotype. To this end, we longitudinally assessed the gene expression profiles of blood-and lymph node-derived CD4 + cells from AGMs and RMs in response to SIVagm and SIVmac infection, respectively, using a genomic microarray platform. The molecular signature of acute infection was characterized, in both species, by strong upregulation of type I IFN-stimulated genes (ISGs). ISG expression returned to basal levels after postinfection day 28 in AGMs but was sustained in RMs, especially in the lymph node-derived cells. We also found that SIVagm induced IFN-α production by AGM cells in vitro and that low IFN-α levels were sufficient to induce strong ISG responses. In conclusion, SIV infection triggered a rapid and strong IFN-α response in vivo in both AGMs and RMs, with this response being efficiently controlled only in AGMs, possibly as a result of active regulatory mechanisms.

We addressed the role of plasmacytoid dendritic cells (PDC) in protection against AIDS in nonpathogenic simian immunodeficiency virus (SIVagm) infection in African green monkeys (AGMs). PDC were monitored in blood and lymph nodes (LNs) starting from day 1 postinfection. We observed significant declines in blood during acute infection. However, PDC then returned to normal levels, and chronically infected AGMs showed no decrease of PDC in blood. There was a significant increase of PDC in LNs during acute infection. Blood PDC displayed only weak alpha interferon (IFN-␣) responses to TLR9 agonist stimulation before infection. However, during acute infection, both blood and LN PDC showed a transiently increased propensity for IFN-␣ production. Bioactive IFN-␣ was detected in plasma concomitant with the peak of viremia, though levels were only low to moderate in some animals. Plasma interleukin 6 (IL-6) and IL-12 were not increased. In conclusion, PDC were recruited to the LNs and displayed increased IFN-␣ production during acute infection. However, increases in IFN-␣ were transient. Together with the lack of inflammatory cytokine responses, these events might play an important role in the low level of T-cell activation which is associated with protection against AIDS in nonpathogenic SIVagm infection.During primary and chronic human immunodeficiency virus type 1 (HIV-1) infection, both subsets of dendritic cells (DC), i.e., myeloid dendritic cells (MDC) and plasmacytoid dendritic cells (PDC), are decreased in the blood (20,36,46). The capacity of PDC to produce IFN-␣ is impaired in acute and chronic HIV-1 infection (13,23,29). Long-term nonprogressors display higher numbers of PDC and a higher capacity for their PDC to produce IFN-␣ than progressors (46). Early profound and persistent depletions of PDC have also been observed in macaques infected with the macaque strain of simian immunodeficiency virus (SIVmac) (4, 40). Different mechanisms have been proposed to explain DC declines, including cell death and homing to lymph nodes (LNs) (4,32,40,50).Here, we investigated the dynamics and function of PDC in blood and LNs during a nonpathogenic infection, i.e., SIVagm infection in African green monkeys (AGMs). AGMs, like other African nonhuman primates, such as mandrills and mangabeys, are natural hosts for SIV and generally do not progress to AIDS despite displaying high levels of plasma and intestinal viral load (VL) (21). Natural hosts for SIV display low levels of T-cell activation, in contrast to HIV-infected humans and SIVmac-infected macaques (6). Exacerbated chronic T-cell activation might drive CD4 T-cell depletion and AIDS (19,22). An immunologic activation set point is established early after HIV-1 infection, and this set point is predictive of the rate at which CD4 ϩ T cells are lost over time (11,49). Innate immune responses acting at the early time points are crucial for T-cell activation profiles. In the present study, we studied whether PDC are recruited to LNs in response to SIVagm and analyzed early cyt...