Death of CD4+ T Cells from Lymph Nodes during Primary SIVmac251 Infection Predicts the Rate of AIDS Progression

Abstract

Immunological and virological events that occur during the earliest stages of SIV infection are now considered to have a major impact on subsequent disease progression. In the present study, we demonstrate a clear correlation between progression to AIDS and the rate of in vitro CD4+ (but not CD8+) T cell death in lymph nodes. The dying CD4+ T cells were effector memory T cells, which are critical for the immune response to pathogens. However, there was no correlation between the rate of the viral replication within lymph nodes and the extent of Fas ligand-mediated death, despite the increased sensitivity of CD4+ T cells to death in response to recombinant human Fas ligand. CD4+ T cell death was caspase and apoptosis-inducing factor independent but was clearly associated with mitochondrion damage. Interestingly, higher expression levels of the active form of Bak, a proapoptotic molecule involved in mitochondrial membrane permeabilization, were observed in SIV-infected macaques progressing more rapidly to AIDS. Finally, we demonstrated that the strain of SIV we used requires CCR5 and BOB/GRP15 molecules as coreceptors and caused death of unstimulated noncycling primary CD4+ T cells. Altogether, these results demonstrate that CD4+ T cell death occurring early after SIV infection is a crucial determinant of progression to AIDS and that it is mediated by the intrinsic death pathway.

AIDS Progression Is Associated with the Emergence of IL-17–Producing Cells Early After Simian Immunodeficiency Virus Infection

“…Caspase-1, a member of the cysteine protease family involved in apoptosis, is involved in the maturation and secretion of IL-18 (35). Therefore, the absence of IL-18 in SIV-infected AGMs could reflect the absence of apoptosis that we and others have described in this nonpathogenic primate model, compared with pathogenic primate models, during both the acute (26) and the chronic phase (24,(43)(44)(45)(46). Thus, a vicious cycle may be generated by the occurrence of apoptotic cells in the tissues of SIV + RMs, favoring not only the expression of IL-18, but also, through their phagocytosis by macrophages and dendritic cells, the production of TGF-b and the absence of TNF-a and IL-1b (47), favoring the emergence of IL-17 + NKT + over IL-17 + CD4 + T cells.…”

Differential CD4 + T-Lymphocyte Apoptosis and Bystander T-Cell Activation in Rhesus Macaques and Sooty Mangabeys during Acute Simian Immunodeficiency Virus Infection

“…Induction of apoptosis in early SIV infection has been shown to be a predictor of later disease progression in SIV-infected rhesus macaques (RM) (24,32). Only a limited number of studies have compared apoptosis in natural and nonnatural hosts during the acute phase of SIV infection.…”

SIV-specific CD8+ T cells express high levels of PD1 and cytokines but have impaired proliferative capacity in acute and chronic SIVmac251 infection

“…HIV-specific CD8 ϩ T cells are less polyfunctional and more sensitive to apoptosis than CD8 ϩ T cells specific for other persistent viral infections, such as cytomegalovirus (CMV). 25,26 In SIV infection, total CD4 ϩ and CD8 ϩ T cells are characterized by increased sensitivity to cell death, 27,28 a phenomenon that predominantly affects uninfected cells. 29 A major target of CD8 ϩ T cells in Mamu-A*01-expressing monkeys is the immunodominant Gag epitope, CM9 (CTPYDINQM; residues 181-189).…”