Mechanisms of apoptosis induction by the HIV-1 envelope

Perfettini, Jean-Luc; Castedo, Maria; Roumier, Thomas; Andréau, Karine; Nardacci, Roberta; Piacentini, Mauro; Kroemer, Guido

doi:10.1038/sj.cdd.4401584

Cited by 140 publications

(142 citation statements)

References 75 publications

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“…mTOR and CD4 + -T-cell loss mTOR activation seems to play a pathogenetic part in the dysregulated apoptosis of CD4 + T cells in HIV-1 patients through gp120-mediated activation of the CD4/CXCR4 (or CCR5)/mTOR/p53 axis [24]. In fact, mTOR can phosphorylate p53 on serine 15 involved in Env-induced syncytial apoptosis [25].…”

Section: Hiv and Its Treatment: Advantages And Some Limits Of Haartmentioning

confidence: 99%

mTOR as a multifunctional therapeutic target in HIV infection

Nicoletti

Fagone

Meroni

et al. 2011

Drug Discovery Today

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Section: Hiv and Its Treatment: Advantages And Some Limits Of Haartmentioning

confidence: 99%

mTOR as a multifunctional therapeutic target in HIV infection

Nicoletti

Fagone

Meroni

et al. 2011

Drug Discovery Today

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“…While HIV envelope glycoprotein has been implicated in the loss of bystander cells by apoptosis, the mechanism by which envelope mediates this process remains highly debated [51]. Early studies indicated that binding of cell surface associated gp120 subunit of envelope on infected cells with uninfected cells leads to apoptosis [52].…”

Section: Mechanisms Of Hiv-1 Gp41 Induced Pathogenesismentioning

confidence: 99%

HIV-1 envelope glycoprotein-mediated fusion and pathogenesis: Implications for therapy and vaccine development

Jacobs

Garg

Viard

et al. 2008

Vaccine

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Our overall goal is to understand how viral envelope proteins mediate membrane fusion and pathogenesis. Membrane fusion is a crucial step in the delivery of the viral genome into the cell resulting in infection. On the other hand, fusion activity of viral envelope glycoproteins expressed in infected cells may cause the demise of uninfected bystander cells by apoptosis. Our general approach is to kinetically resolve steps in the pathway of viral envelope glycoprotein-mediated membrane fusion and to uncover physical parameters underlying those steps using a variety of biochemical, biophysical, virological, and molecular and cell biological techniques. Since HIV fusion involves a complex cascade of interactions of the envelope glycoprotein with two receptors, membrane organization plays an important role and interfering with it may modulate entry. To study this phenomenon, we have either examined cell lines with differential expression of sphingolipids (such as GM3), or altered membrane organization by modifying levels of cholesterol, ceramides, or glycosphingolipids. We show that the localized plasma membrane lipid microenvironment (and not the specific membrane lipids) in the vicinity of CD4 controls receptor mobility and HIV-1 fusion. The complex cascade of conformational changes that must occur to allow virus entry is also a very important target for therapy and vaccine development. We have recently designed and tested peptide analogs composed of chemical spacers and reactive moieties positioned strategically to promote permanent attachment. Using a temperature-arrested state in vitro assay we show evidence for the trapping of a pre-six helix bundle fusion intermediate by a covalent reaction with the inhibitory reactive peptide. Also, using photo-reactive hydrophobic probes we have found ways to inactivate viral envelope glycoproteins while leaving their overall structures intact. Finally, in order to study the envelope glycoprotein effects on pathogenesis, we have used an in vitro model of co-culture of envelope-expressing cells as effectors and CD4+ T cells as targets. We delineated that apoptosis mediated by envelope glycoprotein in bystander cells correlates with transmembrane subunit (gp41)-induced hemifusion. The apoptotic pathway initiated by this interaction involves caspase-3-dependent mitochondrial depolarization and reactive oxygen species production, which depends on the phenotype of the envelope glycoprotein associated with the virus. Taken as a whole, our studies have many different important implications for anti-viral therapies and vaccine development.

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“…In vivo circulating immune complexes and replicationincompetent viruses that contain gp120 could induce cell death in a similar manner. 11 Moreover, during HIV-1 infection, there is an increase of circulating anti-CD4 antibodies and more importantly of soluble gp120, anti-gp120 antibodies, and a large number of defective virions, all of which can lead to a www.nature.com/cdd chronic and significant degree of CD4-mediated activation and cell death in uninfected CD4 þ cells 12,13 Highly active ARV therapy (HAART), combining HIV reverse transcriptase and protease inhibitors, leads to a decrease in plasmatic and lymphoid tissue viral load, that may reach undetectable levels, and a concomitant increase in CD4 T-cell numbers. Several mechanisms are involved in the quantitative restoration of CD4 þ T cells, including homeostatic peripheral proliferation, central (thymic) production of new T cells and increased lymphocyte survival (reviewed by Gougeon 1 ).…”

mentioning

confidence: 99%