Search

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.sup.+] 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.sup.+] 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., Introduction The molecular mechanisms underlying the pathogenesis of HIV infection are still not fully understood. HIV infection is characterized by progressive [CD4.sup.+] T cell depletion and immune cells dysfunctions that [...]

HIV Infects activated CD4+ T cells and induces their depletion. Progressive HIV infection leading to AIDS is fueled by chronic immune hyperactivation, medi-ated by inflammatory cytokines like TNFa. This has been related to intestinal epithe-lial damage and microbial LPS transloca-tion into the circulation. Using 11-color flow cytometry, cell sorting, and cell cul-ture, we investigated the numbers and TNFa production of fully defined circulat-ing dendritic cell and monocyte popula-tions during HIV-1 infection. In 15 viremic, untreated patients, compared with 8 treated, virologically suppressed patients or to 13 healthy blood donors, circulating CD141 (BDCA-3)+ and CD1c (BDCA-1)+ dendritic cell counts were reduced. Conversely, CD14+CD16++ monocyte counts were increased, particularly those expressing M-DC8, while classical CD14++CD16-M-DC8- monocyte num-bers were unchanged. Blood mononu-clear cells from viremic patients pro-duced more TNFa in response to LPS than those from virologically suppressed patients. M-DC8+ monocytes were mostly responsible for this overproduction. More-over, M-DC8+ monocytes differentiated in vitro from classical monocytes using M-CSF and GM-CSF, which is increased in viremic patient's plasma. This M-DC8+ monocyte population, which is involved in the pathogenesis of chronic inflamma-tory diseases like Crohn disease, might thus be considered as a major actor in the immune hyperactivation fueling HIV infec-tion progression. [ABSTRACT FROM AUTHOR]