Membrane Expression of HIV Envelope Glycoproteins Triggers Apoptosis in CD4 Cells

Abstract

The cytopathic effect of HIV-1 and HIV-2 in CD4+ lymphocytes has been shown to be associated with apoptosis or programmed cell death. Using different experimental conditions, we demonstrate here that apoptosis is triggered by cell membrane expression of the mature HIV envelope glycoproteins, gp120-gp41 complex, and their interaction with CD4 receptor molecules. Viral entry alone did not induce apoptosis but virus replication was required in order to produce the gp120-gp41 complex. Indeed, expression of the HIV env gene alone in the CD4+ T cell line (CEM) was sufficient for the induction of apoptosis. In general, syncytium formation and apoptosis induction were closely associated as both events require functional envelope glycoproteins and CD4 molecules. Nevertheless, apoptosis but not syncytium formation was suppressed by a monoclonal antibody against CD4 that does not affect gp120 binding. Furthermore, single-cell killing by apoptosis was observed in infected cell cultures treated with a monoclonal antibody against gp41, which completely abolishes the formation of syncytia. These results indicate that apoptosis is not the consequence of toxic effects induced by the formation of syncytia but is triggered by the HIV envelope glycoproteins. Therefore, cell death during HIV infection in CD4+ lymphocyte cultures is due to a specific event triggered by the gp120-gp41 heterodimer complex programming death in metabolically active cells.

Productive infection and subsequent interaction of CD4-gp120 at the cellular membrane is required for HIV-induced apoptosis of CD4+ T cells

“…This cell surface signalling is also a different mechanism to the one described by Groux et al (1992) where CD4 + T cells isolated from HIV-infected individuals, despite being mostly HIVnegative, were predisposed to undergo apoptosis and some did so when confronted with another immunological challenge such as superantigens. Our results are in agreement with the apoptosis mechanism presented by Laurent-Crawford and collaborators (Laurent-Crawford et al, 1993) where membrane expression of HIV envelope glycoprotein, or in our case productive viral infection, would trigger apoptosis. However, subsequent CD4 engagement by gpl20 in the context of an infected cell would be required according to our observations.…”

“…Moreover, cultured T cell clones are exquisitely susceptible to apoptosis. LaurentCrawford and collaborators have demonstrated that gpl20-gp41 heterodimer complex may be programming cell death in CD4 + lymphocytes (Laurent-Crawford et al, 1993). The expression of the env gene in the lymphoblastoid T cell line CEM was sufficient to induce apoptosis possibly by generating the multimerization of surface CD4.…”

Productive HIV-1 Infection of Primary CD4+ T Cells Induces Mitochondrial Membrane Permeabilization Leading to a Caspase-independent Cell Death

“…HIV-mediated death of productively infected CD4ϩ T cells in vitro has, however, been found to be independent of CD95/CD95L interactions (4 -6), and the possible involvement of other members of the TNF receptor family has not been explored. Several findings suggest that viral proteins encoded by HIV-1 (gp120 envelope glycoprotein, Vpr) may induce death of either infected or uninfected CD4ϩ T cells in productively infected CD4 T cell cultures (22)(23)(24)(25)(26)(27)(28).…”

Genetic analysis of poliovirus protein 3A: characterization of a non-cytopathic mutant virus defective in killing Vero cells.

“…Interestingly, both induction and prevention of apoptosis has been reported in specific cell lines infected with poliovirus (Tolskaya et al, 1995). Apoptosis has also been proven as a major cause of cytopathogenicity in some virus systems (Jeurissen et al, 1992 ;Laurent-Crawford et al, 1993 ;Levine et al, 1993 ;Hinshaw et al, 1994 ;Esolen et al, 1995). In addition, enhancement of cytosolic calcium can trigger the apoptotic response (Bowen, 1993).…”