Enhanced CD4+ cellular apoptosis by CCR5-restricted HIV-1 envelope glycoprotein variants from patients with progressive HIV-1 infection

Jessica Wade, Jasminka Sterjovski, Lachlan Robert Gray, Michael Roche, Lisa Chiavaroli, Anne Ellett, Martin R Jakobsen, Daniel Cowley, Candida da Fonseca Pereira, Nitin Saksena, Bin Wang, Damian F J Purcell, Ingrid Karlsson, Eva Maria Fenyo, Melissa Churchill, Paul R Gorry

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18 Citations (Scopus)

Abstract

CCR5-using (R5) human immunodeficiency virus type 1 (HIV-1) strains cause CD4+ T-cell loss in most infected individuals, but mechanisms underlying cytopathicity of R5 viruses are poorly understood. We investigated mechanisms contributing to R5 envelope glycoprotein (Env)-mediated cellular apoptosis by constructing a panel of retroviral vectors engineered to co-express GFP and R5 Envs derived from two HIV-1-infected subjects spanning asymptomatic (Early, E-R5 Envs) to late stages of infection (Late, L-R5 Envs). The L-R5 Envs induced significantly more cellular apoptosis than E-R5 Envs, but only in Env-expressing (GFP-positive) cells, and only in cells where CD4 and CCR5 levels were limiting. Studies with fusion-defective Env mutants showed induction of apoptosis required membrane-fusing events. Our results provide evidence for an intracellular mechanism of R5 Env-induced apoptosis of CD4+ cells that requires membrane fusion. Furthermore, they contribute to a better understanding of mechanisms involved in CD4+ T-cell loss in subjects experiencing progressive R5 HIV-1 infection.
Original languageEnglish
Pages (from-to)246 - 255
Number of pages10
JournalVirology
Volume396
Issue number2
DOIs
Publication statusPublished - 2010

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