Programmed Cell Death in AIDS-Related HIV and SIV Infections

Abstract

One of the difficulties in understanding the complex pathology of human immunodeficiency virus (HIV) infection is to explain the progressive depletion of the CD4 helper T cell population and consequently the destruction of the immune system. Although cytopathic effects of HIV are observed in vitro, they cannot in vivo account for CD4 T cell depletion because relatively few cells are productively infected. Thus immunological mechanisms must be envisaged. We have found that peripheral blood lymphocytes (PBLs) from asymptomatic HIV-infected individuals are primed for a suicide process known as apoptosis or programmed cell death (PCD). DNA fragmentation characteristic of apoptosis was enhanced by stimulation of lymphocytes with ionomycin, a known inducer of apoptosis in suitably primed cells. Identification of the T cell subpopulations programmed for apoptosis indicated that both CD4+ and CD8+ cells died when cultured without stimulation or when polyclonally stimulated with ionomycin. Activation-induced cell death was also observed after stimulation with self-MHC class II-dependent superantigens, namely bacterial toxins from Staphylococcus (SEB), Streptococcus (ETA), and Myocoplasma (MAM) and under these conditions the CD4+ T cells were preferentially affected. To explore whether new macromolecular synthesis were required for apoptosis, various known inhibitors of apoptosis such as cycloheximide, cyclosporin A, Zn2+, or EGTA were tested. Activation-induced apoptosis was found sensitive to these inhibitors, indicating an active mechanism, but apoptosis observed in nonstimulated cultures was not, suggesting that these cells already contained the complete machinery for death. Prevention of apoptosis could be obtained in the presence of a mixture of cytokines and the minimal signal necessary for this prevention was IL-1 alpha and IL-2. Finally, a correlation between PCD and AIDS-pathogenesis was suggested by the comparison of lymphocytes from lentivirus-infected primates suceptible (SIV-infected macaques) and resistant (HIV-infected chimpanzees) to AIDS. Altogether our results suggest that, during HIV or SIV infection, PCD may contribute in vivo to the deletion of reactive T cells after antigenic stimulation.

Apoptosis in SIV infection

“…Several studies have found that abnormal levels of apoptosis occur both in vitro [41][42][43][44][45][46][47][48][49][50][51] and in vivo 52,53 in CD4 þ and CD8 þ T cells from HIV-1-infected persons. Importantly, the majority of T cells undergoing apoptosis in HIV-infected patients are not infected by the virus; 52,53 this observation led to the definition of 'bystander' apoptosis when referring to apoptosis that is not occurring as a direct cytopathic effect of HIV.…”

A novel mechanism for HIV1-mediated bystander CD4+ T-cell death: neighboring dying cells drive the capacity of HIV1 to kill noncycling primary CD4+ T cells

“…1,2,[8][9][10] The third proposed mechanism is excessive, ongoing immune activation caused by a high, persistent viral antigen load and leading to the activation-induced death of various uninfected immune cells, including CD4 þ T cells. 1,2,4,8,9 Evidence for the involvement of indirect mechanisms of CD4 þ T-cell killing has been provided by the identification in vivo [11][12][13][14][15][16] and ex vivo [17][18][19] of increased number of dying, uninfected immune cells, including CD4 þ T cells, both in HIV1-infected persons and in non-human primate models of pathogenic simian immunodeficiency virus (SIV) infection, that are closely related to HIV. An important question is whether HIV1 may only cause death in activated, cycling CD4 þ T cells, or also in unstimulated noncycling CD4 þ T cells, which represent at any given time point the vast majority of the CD4 þ T cells in HIV1-infected persons.…”

Apoptosis of HIV-specific CD8+ T cells: an HIV evasion strategy

“…Increased in vitro spontaneous, AICD and CD95/Fas-induced apoptosis have been reported in early studies. 26,27,30,31 The involvement of TNFR1 and TNFR2 in apoptosis of CD8 þ T cells from HIVinfected individuals was shown recently. 60 Furthermore, TNFrelated apoptosis-inducing ligand (TRAIL) can mediate in part AICD of CD4 þ and CD8 þ T cells.…”

“…29 Early in vitro studies made apparent that both CD4 þ and CD8 þ T cells from HIV-infected individuals are sensitive to spontaneous apoptosis, activation-induced cell death (AICD) and CD95/Fas-mediated apoptosis. 27,[30][31][32][33] In vivo, this cell death occurs primarily in noninfected bystander cells and rarely in HIV-infected cells. 34,35 Furthermore, CD4 þ and CD8 þ T-cell apoptosis was detected in tonsillar tissues, 36 while a generalized apoptotic phenotype including also B cells and dendritic cells was observed in lymph nodes of HIV patients.…”

“…57,58 Additional evidence supporting the critical role of apoptosis in AIDS progression emerges from studies in SIV-infected macaques where lymphocyte apoptosis was found to be associated with the pathogenicity of lentiviral infection. 31,32 Furthermore, an extensive apoptosis in peripheral lymphoid organs during primary SIV infection was previously found to be predictive of the ability of the immune system to control viral replication and disease progression. 59 In summary, elevated T-cell apoptosis (reviewed elsewhere in this issue) is well established in HIV infection, correlates with disease progression and response to therapy, suggesting a potential important role in the pathogenesis of HIV disease.…”