Induction of CD4-dependent cell fusion by the HTLV-III/LAV envelope glycoprotein

Abstract

Formation of syncytia, with progression to cell death, is a characteristic feature of in vitro cultures of susceptible cells infected with human T-lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV). Viral antigen-positive multinucleated giant cells have also been observed in histological sections from infected individuals. In vitro, formation of these multinucleated giant cells occurs through cell fusion which is dependent on cell-surface expression of the differentiation antigen CD4. Utilizing a recombinant vaccinia virus containing the gene for the envelope glycoprotein of HTLV-III/LAV, we demonstrate that cell-surface expression of this protein, in the absence of other HTLV-III/LAV structural or regulatory proteins, is sufficient to induce CD4-dependent cell fusion, leading to cell death, one of the characteristic manifestations of AIDS (acquired immune deficiency syndrome) virus cytopathology. This process may contribute to the loss of CD4+ T cells seen in AIDS.

HIV-1 Nef Triggers Macrophage Fusion in a p61Hck- and Protease-Dependent Manner

“…Also HIV-1-infected CD4 + lymphocytes form giant cells in vitro, but until now, they have not been observed in AIDS patients. Other mechanisms could account for the remaining MGCs formed with Dnef-HIV-1-infected macrophages (53,(66)(67)(68)(69)(70) [i.e., fusion of HIV-1 infected T cells is in part mediated by interaction of the virally encoded env gene expressed at the plasma membranes of infected cells with CD4 receptors (66,67,(71)(72)(73)(74)(75)]. Because giant macrophages rapidly form upon expression of Nef alone, it indicates that Nef is sufficient to trigger macrophage fusion independently of Env or other viral proteins.…”

Mechanisms of apoptosis induction by the HIV-1 envelope

“…8,11 This underscores the idea that Env is, at least in vitro, the principal apoptosis-inducing protein encoded by the HIV-1 genome. [12][13][14][15] The Env glycoprotein (gp) precursor protein (gp160) undergoes proteolytic maturation to generate gp41 (membrane inserted) and gp120 (membrane inserted or shed from the cell surface). Soluble gp120 can stimulate proapoptotic signal via an action on chemokine receptors (CXCR4 for lymphotropic Env variants, CCR5 for monocytotropic Env variants) 12,16,17 (Figure 1).…”

“…First, the two interacting cells (one which expresses Env and the other that expresses CD4 plus the coreceptor) may not fuse entirely and simply exchange plasma membrane lipids, after a sort of hemifusion process, followed by rapid death. 19 Second, the interaction between the two cells can induce cellular fusion (cytogamy) 14,15,20 followed by nuclear fusion (karyogamy) within the syncytium. 21 Syncytia are condemned to die from apoptosis after a latency phase, presumably when conflicts in cell cycle between the daughter nuclei are detected or when the polyploidy checkpoint is activated.…”

Phenotypic variation in the response to the human immunodeficiency virus among derivatives of the CEM T and WIL-2 B cell lines.

“…All permissive (P + ) strains of CEM underwent rapid fusion (F+) to form multinucleate syncytia when placed in contact with HIVinfected cells, another C134-dependent manifestation of HIV cytopathic effect (29)(30)(31)(32)(33). The converse correlation of C and F phenotypes did not hold among nonpermissive (P-) GEM strains: AC0611a was P -C -and F-, but two other P -C-strains of GEM were F+ .…”

“…The CD4 antigen, through interaction with the glycosylated (13, 32) gp120 envelope protein of HIV, acts as a receptor for free HIV on a subset of T cells, and on cells induced to express CD4 by transfer ofthe CD4 cDNA (1,2,4,(24)(25)(26)(27)(28) . CD4 expression is also necessary for HIV-induced cell fusion (29)(30)(31)(32)(33). Although HIV preferentially infects CD4+ T cells, it also infects cells of different lineages, including monocytes and macrophages (6,(34)(35)(36)(37)(38)(39), B lymphocytes (6,8,39,40), promyelocytes (6), and cells of neural origin (41)(42)(43).…”