title: HIV ENV glycoprotein-mediated bystander apoptosis depends on expression of the CCR5 co-receptor at the cell surface and ENV fusogenic activity.
abstract: HIV-1 infections lead to a progressive depletion of CD4 cells culminating in AIDS. The coreceptor usage by HIV varies from CCR5 (R5) tropic early in infection to CXCR4 (X4) tropic in later infections. Although the coreceptor switch from R5 to X4 tropic HIV is well associated with progression to AIDS, the role of CCR5 in disease progression especially in patients infected exclusively with R5 isolates throughout the disease remains enigmatic. To better understand the role of CCR5 and R5 tropic HIV envelope in AIDS pathogenesis, we asked whether the levels of CCR5 and/or HIV Env-mediated fusion determine apoptosis of bystander cells. We generated CD4(+) T cell lines expressing varying levels of CCR5 on the cell surface to show that CCR5 expression levels correlate with bystander apoptosis induction. The mechanism of apoptosis involved caspase-3 activation and mitochondrial depolarization and was dependent on gp41 fusion activity as confirmed by fusion-restricted gp41 point mutants and use of the fusion inhibitor T20. Interestingly, lower levels of CCR5 were able to support virus replication in the absence of bystander apoptosis. Our findings suggest that R5 HIV-1-mediated bystander apoptosis is dependent on both CCR5 expression levels as well as fusogenic activity of the Env glycoprotein.
authors.affiliation: Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, Texas 79905, USA.
authors.forename: Anjali
authors.initials: A
authors.lastname: Joshi
authors.forename: Alice M
authors.initials: AM
authors.lastname: Nyakeriga
authors.forename: Revathi
authors.initials: R
authors.lastname: Ravi
authors.forename: Himanshu
authors.initials: H
authors.lastname: Garg
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D024201:Bystander Effect; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D000077560:Enfuvirtide; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation; D015700:HIV Envelope Protein gp41 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D023581:HIV Fusion Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D010446:Peptide Fragments / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000096:biosynthesis* / Q000235:genetics; D056189:Viral Tropism / Q000187:drug effects / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D019713:Receptors, CCR5; C514787:gp41 protein, Human immunodeficiency virus 1; D000077560:Enfuvirtide; C505407:CASP3 protein, human; D053148:Caspase 3