HIV envelope-mediated, CCR5/α4β7-dependent killing of CD4-negative γδ T cells which are lost during progression to AIDS

Abstract

HIV infects and replicates in CD4؉ T cells but effects on host immunity and disease also involve depletion, hyper-activation, and modification of CD4-negative cell populations. In particular, the depletion of CD4-negative ␥␦ T cells is common to all HIV؉ individuals. We found that soluble or cell-associated envelope glycoproteins from CCR5-tropic strains of HIV could bind, activates the p38-caspase pathway, and induce the death of ␥␦ cells. Envelope binding requires integrin IntroductionHIV evades the immune response and establishes persistent infection by depleting lymphocyte subsets and altering pathways for cellular maturation or activation. 1 CD4 ϩ T cells are targets for productive virus infection which causes cell death. 2,3 Other cell subsets can be depleted without productive infection; these include B cells, 4 NK cells, 5-7 ␥␦ T cells [8][9][10][11] and uninfected, bystander CD4 T cells. [12][13][14] Loss of uninfected cells is due to indirect effects of HIV which are important mechanisms for immune deficiency and disease leading to AIDS.Pathogenesis of HIV and simian immunodeficiency virus (SIV) have been linked to increased apoptosis of uninfected cells. Comparing HIV infection with virulent SIV (rhesus) or nonvirulent SIV (African green macaques) showed that apoptosis in CD4 ϩ T cells was an identifying characteristic of pathogenic infections. 15 Sooty mangabeys displayed limited bystander cell killing despite high viremia, consistent with their natural resistance to disease. 16,17 Increased levels of Fas 18 or PD-1 19 were associated with cell death or dysfunction. Antibody blocking of Fas ligand 20,21 or PD-1 22 slowed disease by preserving CD4 ϩ central memory or CD8 ϩ CTL, respectively.The roles for viral proteins in killing of uninfected, bystander cells are poorly understood. Previous studies suggested that HIV encodes several apoptogenic proteins with potential to cause cell death, including envelope, Vpr, Tat, and Nef, 23-26 but it is not known whether they are present at sufficient levels in uninfected cells. We do know that envelope is a potent inducer of apoptosis 7,13,14,26,27 but it is not clear how the protein binds and signals CD4-negative cells which form a significant proportion of cells lost to indirect effects of HIV. Cell depletion through indirect effects (noninfectious mechanisms) is apparent in the loss of phosphoantigen-responsive V␥2V␦2 ϩ T cells (also termed V␥9V␦2 ϩ T cells in an alternate nomenclature) that normally comprise 1-4% of circulating lymphocytes and 75% of all circulating ␥␦ T cells in healthy individuals. 28,29 HIV-associated loss of V␥2V␦2 cells was postulated to involve apoptosis. 30 In this study, we found that R5 tropic HIV envelope glycoprotein induced significant death of CD4-negative V␥2V␦2 T cells.Envelope binding and signaling may be an important mechanism for depleting V␥2V␦2 cells during HIV disease. Methods PBMC and tumor cell linesWhole blood was obtained from healthy human volunteers with written informed consent in accordance with the Declaratio...

The Potential Role of CD16+Vγ2Vδ2 T Cell-Mediated Antibody-Dependent Cell-Mediated Cytotoxicity in Control of HIV Type 1 Disease

“…Consistent with previous studies, 13,27 we found the Vd2 T cells declined at least as rapidly as CD4 T cells in early HIV infection, accompanied by the decreased IPP-responsive cells in the CD16 -Vd2 T cell subset. However, with a strong capacity for degranulation, the CD16 + Vd2 T cells from the early-infected group maintained cytotoxic Vd2 T cells as the potentially efficient ADCC effectors.…”

“…They also observed the highest level of HIV envelope-induced cell death in Vd2 T cells when exposed to phosphoantigen, which suggests that phosphoantigen activation might be the reason for the specific loss of the Vc2Jc1.2 Vd2 T cell subpopulation. 27 This finding may partially explain the different status of the two functional Vd2 T cells in early HIV-1 infection: the preservation of the functional Vd2 T cells responding to Fc targets, but not to IPP, in early HIV-1infection was probably due to the barely phosphoantigen-activated CD16 + Vd2 T cell subset. A strong and consistent relationship between viral load and the level of either CD4 + or CD8 + T cell activation has been found during early HIV infection.…”

Binding of HIV-1 virions to α4β7 expressing cells and impact of antagonizing α4β7 on HIV-1 infection of primary CD4+ T cells

“…Recent studies indicate that HIV-1 envelope glycoprotein (Env) gp120 is capable of interacting with integrin α 4 β 7 to potentially increase viral infection (Arthos J, et al, 2008;Cicala C, et al, 2009;Darc M, et al, 2011;Li H, et al, 2011;Nawaz F, et al, 2011;Richardson S I, et al, 2013;Tjomsland V, et al, 2013). α 4 β 7 is expressed on lymphoid cells and mediates cell homing to gut-associated lymphoid tissue (GALT), the dominant site of CD4 + T cell depletion shortly after HIV-1 acquisition and local propagation (Berlin C, et al, 1993;Mehandru S, et al, 2004;Sattentau Q, 2008;Veazey R S, et al, 1998).…”

HIV-1-Induced Impairment of Dendritic Cell Cross Talk with γδ T Lymphocytes

“…In this regard, it has been reported that direct interaction of IPP-expanded ␥␦ T lymphocytes with R5 HIV-1 envelope results in CCR5-␣4␤7-mediated cell death, and this mechanism has been proposed to contribute to the depletion of this cell population in AIDS patients (14,47). In the present work, we report that the direct stimulation of freshly isolated ␥␦ T cells with infectious R5 HIV-1 virions before TCR engagement does not affect their capacity to become fully activated and to expand in response to antigens.…”