Distinct Mechanisms of CD4 + and CD8 + T-Cell Activation and Bystander Apoptosis Induced by Human Immunodeficiency Virus Type 1 Virions

Abstract

ABSTRACT Apoptosis of uninfected bystander T cells contributes to T-cell depletion during human immunodeficiency virus type 1 (HIV-1) infection. HIV-1 envelope/receptor interactions and immune activation have been implicated as contributors to bystander apoptosis. To better understand the relationship between T-cell activation and bystander apoptosis during HIV-1 pathogenesis, we investigated the effects of the highly cytopathic CXCR4-tropic HIV-1 variant ELI6 on primary CD4 + and CD8 + T cells. Infection of primary T-cell cultures with ELI6 induced CD4 + T-cell depletion by direct cell lysis and bystander apoptosis. Exposure of primary CD4 + and CD8 + T cells to nonreplicating ELI6 virions induced bystander apoptosis through a Fas-independent mechanism. Bystander apoptosis of CD4 + T cells required direct contact with virions and Env/CXCR4 binding. In contrast, the apoptosis of CD8 + T cells was triggered by a soluble factor(s) secreted by CD4 + T cells. HIV-1 virions activated CD4 + and CD8 + T cells to express CD25 and HLA-DR and preferentially induced apoptosis in CD25 + HLA-DR + T cells in a CXCR4-dependent manner. Maximal levels of binding, activation, and apoptosis were induced by virions that incorporated MHC class II and B7-2 into the viral membrane. These results suggest that nonreplicating HIV-1 virions contribute to chronic immune activation and T-cell depletion during HIV-1 pathogenesis by activating CD4 + and CD8 + T cells, which then proceed to die via apoptosis. This mechanism may represent a viral immune evasion strategy to increase viral replication by activating target cells while killing immune effector cells that are not productively infected.