Partial activation and induction of apoptosis in CD4(+) and CD8(+) T lymphocytes by conformationally authentic noninfectious human immunodeficiency virus type 1

Increased levels of apoptosis are seen in human immunodeficiency virus (HIV ) infection, and this has been proposed as an important mechanism contribut ing to HIV pathogenesis. However, interpretation of in vitro studies aimed at understanding HIV-related apoptosis has been complicated by the use of h igh concentrations of recombinant proteins or by direct cytopathic effects of replicating virus. We have developed an Inactivation procedure that dest roys retroviral infectivity while preserving the structural and functional integrity of the HIV surface proteins, These noninfectious virions interact authentically dth target cells, providing a powerful tool to dissect mecha nisms of HIV pathogenesis that do or do not require viral replication, Noni nfectious CXCR4-tropic HIV-1 virions, but not microvesicles, partially acti vated freshly isolated CD4(+) and CD8(+) peripheral blood mononuclear cell T lymphocytes to express FasL and Fas, but not CD69 or CD25 (interleukin-2 receptor alpha) and eventually die via apoptosis starting 1 to 6 days poste xposure. These effects required conformationally. intact virions, as heat-d enatured virions or equivalent amounts of recombinant gp120 did not induce apoptosis, The maximal apoptotic effect was dependent on major histocompati bility complex (MHC) class II proteins being present on the virion, but was not MHC restricted. The results suggest that the immunopathogenesis of HIV infection may not depend solely on direct cytopathic effects of HIV replic ation, but that effects due to noninfectious HIV-1 virions may also contrib ute importantly.