Vpr R77Q is associated with long-term nonprogressive HIV infection and impaired induction of apoptosis.
The absence of immune defects that occurs in the syndrome of long-term nonprogressive (LTNP) HIV infection offers insights into the pathophysiology of HIV-induced immune disease. The (H[F/S]RIG)(2) domain of viral protein R (Vpr) induces apoptosis and may contribute to HIV-induced T cell depletion. We demonstrate a higher frequency of R77Q Vpr mutations in patients with LTNP than in patients with progressive disease. In addition, T cell infections using vesicular stomatitis virus G (VSV-G) pseudotyped HIV-1 Vpr R77Q result in less (P = 0.01) T cell death than infections using wild-type Vpr, despite similar levels of viral replication. Wild-type Vpr-associated events, including procaspase-8 and -3 cleavage, loss of mitochondrial transmembrane potential (deltapsi(m)), and DNA fragmentation factor activation are attenuated by R77Q Vpr. These data highlight the pathophysiologic role of Vpr in HIV-induced immune disease and suggest a novel mechanism of LTNP.
Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
Julian J
JJ
Lum
Oren J
OJ
Cohen
Zilin
Z
Nie
Joel G
JG
Weaver
Timothy S
TS
Gomez
Xiao-Jian
XJ
Yao
David
D
Lynch
André A
AA
Pilon
Nanci
N
Hawley
John E
JE
Kim
Zhaoxia
Z
Chen
Michael
M
Montpetit
Jaime
J
Sanchez-Dardon
Eric A
EA
Cohen
Andrew D
AD
Badley
D019943:Amino Acid Substitution; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D018791:CD4 Lymphocyte Count; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005787:Gene Frequency; D016336:Gene Products, vpr / Q000235:genetics* / Q000494:pharmacology; D015658:HIV Infections / Q000235:genetics / Q000821:virology; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D019169:Jurkat Cells; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics; D054325:vpr Gene Products, Human Immunodeficiency Virus
D016336:Gene Products, vpr; D010446:Peptide Fragments; D054325:vpr Gene Products, Human Immunodeficiency Virus; D020169:Caspases