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Enhanced CD4+ cellular apoptosis by CCR5-restricted HIV-1 envelope glycoprotein variants from patients with progressive HIV-1 infection |
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| Authors: | Jessica Wade,Jasminka Sterjovski,Lachlan Gray,Michael Roche,Lisa Chiavaroli,Martin R. Jakobsen,Candida da Fonseca Pereira,Nitin Saksena,Damian F.J. Purcell,Eva-Maria Fenyö ,Paul R. Gorry |
| Affiliation: | a Center for Virology, Burnet Institute, Melbourne, Victoria, Australia b Department of Microbiology and Immunology, University of Melbourne, Melbourne, Victoria, Australia c Department of Medicine, Monash University, Melbourne, Victoria, Australia d Monash Micro Imaging, Monash University, Melbourne, Victoria, Australia e Westmead Millennium Institute, Westmead, New South Wales, Australia f Lund University, Lund, Sweden |
| 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. |
| Keywords: | HIV-1 Env CD4 CCR5 Apoptosis Active caspase-3 |
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