Suppression of HIV-1 transcription and replication by a Vpr mutant.
Vpr, the 96 amino acid long protein represents one of the auxiliary proteins of human immunodeficiency virus type-1 (HIV-1), which exhibits the ability to increase the rate of replication of the virus in T cells. Structurally, this protein is composed of several regions such as the acidic domain with alpha helix at the amino terminus, leucine-isoleucine-rich domain (LR) near the carboxyl terminus and an arginine-rich domain at the C-terminus. Here, we evaluated the ability of wild-type and a spectrum of Vpr mutants with altered amino acid residues within the three major domains of Vpr to regulate of transcription of the HIV-1 LTR. Our results revealed that alterations of amino acids within the LR domain at position 73 from arginine to serine, renders Vpr defective in stimulating transcription of the viral promoter in human T-lymphocytic and astrocytic cells. Mutations within the N- and C-terminal domains had little or no effect on the transcriptional activity of Vpr. Of interest, ectopic expression of this mutant protein exerts a negative effect on the ability of wild-type Vpr, as well as the viral transactivator, Tat, in augmenting viral gene transcription. Production of the mutant Vpr interferes with the replication of the wild-type and delta Vpr virus in the cells. Accordingly, a Vpr mutant virus containing the transition of arginine to serine at position 73 exhibited an inhibitory effect on the replication of wild-type virus. Our results provide a new avenue for the utilization of the variant of the HIV-1 regulatory protein, Vpr, in suppressing replication of the viral genome in infected cells.
Sawaya
B E
BE
Center for NeuroVirology and NeuroOncology, MCP Hahnemann University, Philadelphia, PA 19102, USA.
Khalili
K
K
Rappaport
J
J
Serio
D
D
Chen
W
W
Srinivasan
A
A
Amini
S
S
D019943:Amino Acid Substitution; D001253:Astrocytes; D002478:Cells, Cultured; D016336:Gene Products, vpr; D015316:Genetic Therapy / Q000379:methods; D015658:HIV Infections / Q000628:therapy; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D014158:Transcription, Genetic; D014779:Virus Replication / Q000235:genetics*; D054325:vpr Gene Products, Human Immunodeficiency Virus
D016336:Gene Products, vpr; D054325:vpr Gene Products, Human Immunodeficiency Virus