title: Enhanced CD4+ cellular apoptosis by CCR5-restricted HIV-1 envelope glycoprotein variants from patients with progressive HIV-1 infection.
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.
authors.affiliation: Center for Virology, Burnet Institute, Melbourne, Victoria, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Wade
authors.forename: Jasminka
authors.initials: J
authors.lastname: Sterjovski
authors.forename: Lachlan
authors.initials: L
authors.lastname: Gray
authors.forename: Michael
authors.initials: M
authors.lastname: Roche
authors.forename: Lisa
authors.initials: L
authors.lastname: Chiavaroli
authors.forename: Anne
authors.initials: A
authors.lastname: Ellett
authors.forename: Martin R
authors.initials: MR
authors.lastname: Jakobsen
authors.forename: Daniel
authors.initials: D
authors.lastname: Cowley
authors.forename: Candida da Fonseca
authors.initials: Cda F
authors.lastname: Pereira
authors.forename: Nitin
authors.initials: N
authors.lastname: Saksena
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Damian F J
authors.initials: DF
authors.lastname: Purcell
authors.forename: Ingrid
authors.initials: I
authors.lastname: Karlsson
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Fenyö
authors.forename: Melissa
authors.initials: M
authors.lastname: Churchill
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gorry
mesh_terms: 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
chemical_list: D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5