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

Abstract

CD4 þ T-cell death is a crucial feature of AIDS pathogenesis, but the mechanisms involved remain unclear. Here, we present in vitro findings that identify a novel process of HIV1 mediated killing of bystander CD4 þ T cells, which does not require productive infection of these cells but depends on the presence of neighboring dying cells. X4-tropic HIV1 strains, which use CD4 and CXCR4 as receptors for cell entry, caused death of unstimulated noncycling primary CD4 þ T cells only if the viruses were produced by dying, productively infected T cells, but not by living, chronically infected T cells or by living HIV1-transfected HeLa cells. Inducing cell death in HIV1-transfected HeLa cells was sufficient to obtain viruses that caused CD4 þ T-cell death. The addition of supernatants from dying control cells, including primary T cells, allowed viruses produced by living HIV1-transfected cells to cause CD4 þ Tcell death. CD4 þ T-cell killing required HIV1 fusion and/or entry into these cells, but neither HIV1 envelope-mediated CD4 or CXCR4 signaling nor the presence of the HIV1 Nef protein in the viral particles. Supernatants from dying control cells contained CD95 ligand (CD95L), and antibody-mediated neutralization of CD95L prevented these supernatants from complementing HIV1 in inducing CD4 þ T-cell death. Our in vitro findings suggest that the very extent of cell death induced in vivo during HIV1 infection by either virus cytopathic effects or immune activation may by itself provide an amplification loop in AIDS pathogenesis. More generally, they provide a paradigm for pathogen-mediated killing processes in which the extent of cell death occurring in the microenvironment might drive the capacity of the pathogen to induce further cell death.

Mitochondrial membrane potential and apoptosis of blood mononuclear cells in untreated HIV‐1 infected patients

“…The percentage of apoptotic PBMC detected by Annexin V staining was significantly higher in HIVinfected patients than in HIV-negative controls. This is in accordance with previous studies showing increased apoptosis of PBMC using different markers of apoptosis [38,39].…”

“…The percentage of apoptotic PBMC detected by Annexin V staining was significantly higher in HIVinfected patients than in HIV-negative controls. This is in accordance with previous studies showing increased apoptosis of PBMC using different markers of apoptosis [38,39].For the first time we could demonstrate a highly significant negative correlation between the DC m and the percentage of apoptotic PBMC in HIV-infected, therapy-naïve patients: more PBMC were apoptotic when DC m was reduced. This could be seen in HIV-positive and HIV-negative study participants, but was more pronounced under HIV infection.…”

“…Induction and inhibition of apoptosis is complex and HIV replication itself is only one possible trigger besides the general immune activation during HIV infection [7,42]. The depletion of the CD4 T-cell compartment is explained mainly by apoptosis of uninfected cells caused by indirect mechanisms and syncytia formation [7,38,39]. HIV infection can result in inhibition of apoptosis by modulating the mitochondrial pathway of apoptosis independently from active viral replication [43].…”

CD95 ligand-dependant endothelial cell death initiates oral mucosa damage in a murine model of acute graft versus host disease

“…We have recently documented the in vitro release of such CD95L-bearing microvesicles by human lymphocytes that are undergoing apoptosis. 45 However, these microvesicles acted as cofactors for apoptosis induction were not sufficient by themselves to cause cell death, at least in our in vitro model system. 45 Therefore, it remains to be assessed, whether in addition to the involvement of CD95L expressed and/or released by activated allogeneic lymphocytes, other effector mechanisms may cooperate with CD95L in the induction of the early vascular lesions during aGVHD.…”

“…45 However, these microvesicles acted as cofactors for apoptosis induction were not sufficient by themselves to cause cell death, at least in our in vitro model system. 45 Therefore, it remains to be assessed, whether in addition to the involvement of CD95L expressed and/or released by activated allogeneic lymphocytes, other effector mechanisms may cooperate with CD95L in the induction of the early vascular lesions during aGVHD. Although perforin has been described as a major effector of graft-versus-leukemia (GVL) reactions rather than of aGVHD, 4,20,21 it has also been reported to synergize with CD95L in the induction of epithelial lesions in the skin and liver during aGVHD.…”