Partial Activation and Induction of Apoptosis in CD4⁺and CD8⁺T Lymphocytes by Conformationally Authentic Noninfectious Human Immunodeficiency Virus Type 1

Abstract

Increased levels of apoptosis are seen in human immunodeficiency virus (HIV) infection, and this has been proposed as an important mechanism contributing to HIV pathogenesis. However, interpretation of in vitro studies aimed at understanding HIV-related apoptosis has been complicated by the use of high concentrations of recombinant proteins or by direct cytopathic effects of replicating virus. We have developed an inactivation procedure that destroys retroviral infectivity while preserving the structural and functional integrity of the HIV surface proteins. These noninfectious virions interact authentically with target cells, providing a powerful tool to dissect mechanisms of HIV pathogenesis that do or do not require viral replication. Noninfectious CXCR4-tropic HIV-1 virions, but not microvesicles, partially activated 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 4 to 6 days postexposure. These effects required conformationally intact virions, as heat-denatured virions or equivalent amounts of recombinant gp120 did not induce apoptosis. The maximal apoptotic effect was dependent on major histocompatibility 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 replication, but that effects due to noninfectious HIV-1 virions may also contribute importantly.

Regulation of TNF-related apoptosis-inducing ligand on primary CD4 + T cells by HIV-1: Role of type I IFN-producing plasmacytoid dendritic cells

“…Our results show that free gp120 or gp160 are not sufficient to induce type I IFN, raising the possibility that the conformation of gp120 on HIV-1 particles or its combination with other envelope molecules may be important (32). Previous studies suggest that native virion-associated gp120 may be more potent than soluble monomeric recombinant gp120 in inducing effects dependent on authentic interactions with cell surface receptors (33).…”

A novel mechanism for HIV1-mediated bystander CD4+ T-cell death: neighboring dying cells drive the capacity of HIV1 to kill noncycling primary CD4+ T cells

“…25,26,30,31 Incubation of noncycling, primary CD4 þ T cells with X4-tropic HIV1 viral particles has been previously reported to cause CD4 þ T-cell death, after a delay of 3-4 days. 32,33 The aims of our study were first to confirm this latter finding, and then to investigate the mechanisms involved. Here we show that the presence of dying cells in the HIV1-producing cell culture -which is the source of the viral particles -is a crucial, previously unsuspected cofactor required for the HIV1 particles to cause bystander CD4 þ T-cell killing.…”

HIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors by Toll-like receptor 7-induced IFN-α

“…More than 99% of HIV-1 particles detected in the circulation are not productively infectious (32) but, as previously suggested, might contribute to HIV-induced immunopathogenesis (20,33). For this reason, our investigations have included the effects of noninfectious AT-2 HIV-1 on TRAIL-mediated apoptosis of CD4 ϩ T cells (20).…”