title: Genetic signatures of HIV-1 envelope-mediated bystander apoptosis.
abstract: The envelope (Env) glycoprotein of HIV is an important determinant of viral pathogenesis. Several lines of evidence support the role of HIV-1 Env in inducing bystander apoptosis that may be a contributing factor in CD4(+) T cell loss. However, most of the studies testing this phenomenon have been conducted with laboratory-adapted HIV-1 isolates. This raises the question of whether primary Envs derived from HIV-infected patients are capable of inducing bystander apoptosis and whether specific Env signatures are associated with this phenomenon. We developed a high throughput assay to determine the bystander apoptosis inducing activity of a panel of primary Envs. We tested 38 different Envs for bystander apoptosis, virion infectivity, neutralizing antibody sensitivity, and putative N-linked glycosylation sites along with a comprehensive sequence analysis to determine if specific sequence signatures within the viral Env are associated with bystander apoptosis. Our studies show that primary Envs vary considerably in their bystander apoptosis-inducing potential, a phenomenon that correlates inversely with putative N-linked glycosylation sites and positively with virion infectivity. By use of a novel phylogenetic analysis that avoids subtype bias coupled with structural considerations, we found specific residues like Arg-476 and Asn-425 that were associated with differences in bystander apoptosis induction. A specific role of these residues was also confirmed experimentally. These data demonstrate for the first time the potential of primary R5 Envs to mediate bystander apoptosis in CD4(+) T cells. Furthermore, we identify specific genetic signatures within the Env that may be associated with the bystander apoptosis-inducing phenotype.
authors.affiliation: From the Center of Excellence for Infectious Diseases, Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, Texas 79905.
authors.forename: Anjali
authors.initials: A
authors.lastname: Joshi
authors.forename: Raphael T C
authors.initials: RT
authors.lastname: Lee
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mohl
authors.forename: Melina
authors.initials: M
authors.lastname: Sedano
authors.forename: Wei Xin
authors.initials: WX
authors.lastname: Khong
authors.forename: Oon Tek
authors.initials: OT
authors.lastname: Ng
authors.forename: Sebastian
authors.initials: S
authors.lastname: Maurer-Stroh
authors.forename: Himanshu
authors.initials: H
authors.lastname: Garg
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000473:pathology / Q000821:virology*; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology*; D024201:Bystander Effect / Q000235:genetics* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000821:virology; D002478:Cells, Cultured; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology; D015700:HIV Envelope Protein gp41 / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000235:genetics*; D006367:HeLa Cells; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D010641:Phenotype; D010802:Phylogeny; D019713:Receptors, CCR5 / Q000276:immunology; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; C584933:CCR5 protein, human; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D019713:Receptors, CCR5; D054299:env Gene Products, Human Immunodeficiency Virus; C514793:gp120 protein, Human immunodeficiency virus 1
keywords: AIDS; Apoptosis; Genetics; HIV; Infectious Diseases; Retrovirus; Virology