Distinct mechanisms of CD4+ and CD8+ T-cell activation and bystander apoptosis induced by human immunodeficiency virus type 1 virions.
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.
Holm
Geoffrey H
GH
Dana-Farber Cancer Institute, JFB 816, 44 Binney St., Boston, MA 02115, USA.
Gabuzda
Dana
D
D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D002478:Cells, Cultured; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000378:metabolism / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D019718:Receptors, CXCR4 / Q000378:metabolism; D014771:Virion / Q000378:metabolism / Q000502:physiology*; D014774:Virulence / Q000276:immunology; D014779:Virus Replication
D019718:Receptors, CXCR4