Mechanisms of bystander T cell apoptosis in HIV-1 infection

Human immunodeficiency virus type 1 (HIV-1) infection causes progressive loss of CD4+ T cells, leading to AIDS. HIV-1 also causes depletion of CD8+ T cells and damage to the CNS. Direct cytopathic effects and apoptosis of uninfected bystander CD4+ T cells contribute to CD4+ T cell depletion. Additionally, bystander apoptosis of CD8+ T cells and neurons plays an important role in AIDS pathogenesis. The viral and host mechanisms that lead to bystander apoptosis are poorly understood. The HIV-1 envelope glycoproteins (Env) cause direct cytopathic effects, and have also been implicated in causing bystander apoptosis. To better understand mechanisms of HIV-1 pathogenesis, we investigated the role of the HIV-1 Env in bystander apoptosis. Exposure to nonreplicating HIV-1 virions activated CD4+ and CD8+ T cells in a CXCR4-dependent manner. The activated T cells then proceeded to die via apoptosis through a Fas-independent mechanism. Bystander apoptosis of CD4+ T cells required direct contact with virions and Env/CXCR4 binding, whereas apoptosis of CD8+ T cells was triggered by a soluble factor(s) secreted by CD4+ T cells. Maximal levels of binding, activation, and apoptosis were induced by virions that incorporated MHC Class II and B7-2 into the viral membrane. Changes in Env that increase affinity for CD4 or CCR5 or increase coreceptor binding site exposure enhanced the ability of HIV-1 virions to induce bystander apoptosis. HIV-1 virions with mutant Envs that bind CXCR4 but are defective for CD4 binding or membrane fusion induced apoptosis in CD4+ T cells, whereas CXCR4 binding-defective mutants did not. These results demonstrate that nonreplicating HIV-1 virions induce activation and apoptosis through a coreceptor-dependent pathway that does not require Env/CD4 signaling or membrane fusion. This may represent a viral immune evasion strategy to increase viral replication in activated T cells while inducing apoptosis in immune effector cells that are not productively infected. Thus, therapeutic strategies to block interactions between HIV-1 virions and CXCR4 may reduce both activation and depletion of CD4+ and CD8+ T cells in AIDS patients.