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.
Highlights
Determinants of HIV-1 Env-mediated apoptosis remain poorly understood
It is proposed that the loss of CD4 cells during HIV infection is due to the process of bystander apoptosis [2]
This is supported by early studies conducted by Finkel et al [9], who demonstrated that the majority of cells undergoing apoptosis during HIV infection are not infected but are in close proximity to infected cells
Summary
Determinants of HIV-1 Env-mediated apoptosis remain poorly understood. Results: We studied the bystander apoptosis-inducing activity of a panel of primary HIV 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. We developed a high throughput assay to study a panel of primary patient-derived HIV Envs for their bystander apoptosis-inducing activity and determined its correlation with both phenotypic and genotypic characteristics of the Envs. These included virus infectivity, sensitivity to neutralizing antibodies, putative N-glycosylation sites, Env charge, and association of specific residues in the Env with bystander apoptosis. To the best of our knowledge, this is the first study aimed at studying the bystander apoptosis-inducing activity of a large panel of primary Envs utilizing a high throughput assay and correlating this phenomenon with specific Env signatures
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