Mechanisms Associated with Thymocyte Apoptosis Induced by Simian Immunodeficiency Virus

Abstract

Despite considerable research, the mechanisms by which HIV disrupts thymic function remain controversial. We have described the phenotypic changes that occur in the thymus of SIV-infected macaques during acute SIV infection. In this study, we analyzed the effects of SIV infection on apoptotic pathways in thymic tissue from newborn macaques infected with SIV. Thymocyte apoptosis was accompanied by a modest increase in surface Fas expression, a profound decrease in the frequency of bcl-2-positive cells, as well as the amount of bcl-2 per cell. With control of viral replication, levels of bcl-2 and Fas returned to baseline together with a return to basal levels of apoptosis. In the thymus, SIV infection resulted in depletion of CD4+CD8+ thymocytes, an increase in apoptosis of thymocytes, and a down-regulation of MHC class I molecules. These changes peaked 14–21 days after infection at or just after peak viremia. This data further suggests disruption of the antiapoptotic pathway regulated by bcl-2 plays a critical role in SIV-induced apoptosis of thymocytes.

Acute Thymic Involution and Mechanisms for Recovery

“…During infection of newborn rhesus macaques with SIV, ATI-associated events (including enhanced death and depletion of thymocytes by various apoptotic mechanisms) very similar to those described in HIV-infected humans (Rosenzweig et al 2000) are observed. In conclusion, an appropriate animal model system is indispensable for the proper identification of mechanisms involved in ATI during such cases of viral infections.…”

Caspase-dependent and -independent T-cell death pathways in pathogenic simian immunodeficiency virus infection: relationship to disease progression

“…20,21 Despite the considerable effort directed at elucidating the mechanisms responsible for apoptosis in HIV-1 infection in humans, very little information has been obtained from primate models of lentivirus infection and the available data principally concern the acute phase. [22][23][24] In particular, no study has addressed the question of the relative contributions made by the extrinsic and intrinsic pathways to programmed T-cell death during SIV infection. In addition, no attempt has been made to evaluate the correlation between disease progression and the probability of T cells undergoing apoptosis after CD95 ligation.…”

Timely triggering of homeostatic mechanisms involved in the regulation of T-cell levels in SIVsm-infected sooty mangabeys

“…[1][2][3] At the same time, dysfunction in the CD4 ϩ T-cell restorative abilities induced by HIV/SIV infection also contributes to progressive decline in CD4 ϩ T cells. [4][5][6] Thus, one important aspect of pathogenic HIV infection in humans and SIV infection in macaques is the loss of T-cell homeostasis, an imbalance between the rate of CD4 ϩ T-cell production and their death. 4 Growing evidence indicates that cytokines are involved in the maintenance of T-cell homeostasis in the periphery.…”