Enhanced CD4+ cellular apoptosis by CCR5-restricted HIV-1 envelope glycoprotein variants from patients with progressive HIV-1 infection.
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.
Wade
Jessica
J
Center for Virology, Burnet Institute, Melbourne, Victoria, Australia.
Sterjovski
Jasminka
J
Gray
Lachlan
L
Roche
Michael
M
Chiavaroli
Lisa
L
Ellett
Anne
A
Jakobsen
Martin R
MR
Cowley
Daniel
D
Pereira
Candida da Fonseca
Cda F
Saksena
Nitin
N
Wang
Bin
B
Purcell
Damian F J
DF
Karlsson
Ingrid
I
Fenyö
Eva-Maria
EM
Churchill
Melissa
M
Gorry
Paul R
PR
D017209:Apoptosis / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology / Q000821:virology*; D003001:Cloning, Molecular; D018450:Disease Progression; D015699:HIV Envelope Protein gp120 / Q000235:genetics* / Q000502:physiology; D015658:HIV Infections / Q000503:physiopathology / Q000821:virology*; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D019713:Receptors, CCR5 / Q000502:physiology*; D014161:Transduction, Genetic; D014774:Virulence; D053585:Virus Attachment; D053586:Virus Internalization
D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5