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J Biol Chem. 2014 Jan 31;289(5):2497-514. doi: 10.1074/jbc.M113.514018. Epub 2013 Nov 21.

Genetic signatures of HIV-1 envelope-mediated bystander apoptosis.

Author information

1
From the Center of Excellence for Infectious Diseases, Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, Texas 79905.

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.

KEYWORDS:

AIDS; Apoptosis; Genetics; HIV; Infectious Diseases; Retrovirus; Virology

PMID:
24265318
PMCID:
PMC3908386
DOI:
10.1074/jbc.M113.514018
[Indexed for MEDLINE]
Free PMC Article

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