Transdominant activity of human immunodeficiency virus type 1 Vpr with a mutation at residue R73.
The 96-amino-acid-long human immunodeficiency virus type 1 virion-encoded accessory protein Vpr is of particular interest, as this protein, which is found in association with viral particles, can exert a regulatory effect on both virus replication and host cell function. Evidently, Vpr, through interaction with several host regulatory proteins, can modulate transcription from the viral long terminal repeat promoter. Expression of Vpr in cells results in deregulation of cell proliferation during the cell cycle pathway at the G(2) stage. Vpr has unique structural features consisting of multiple functional domains. In this study, we have focused on the leucine/isoleucine-rich domain near the carboxyl terminus of Vpr at residue 73 (arginine) and have demonstrated that alterations at this residue result in ablation of transcriptional activity of Vpr and its ability to block cell cycle events at the G(2) stage. Interestingly, substitution mutations at R73 have resulted in a peptide with dominant negative activities on wild-type functions in transcription and host proliferation events. Results from in vitro and in vivo protein-protein interaction studies have revealed that functionally inactive mutant Vpr can be associated with wild-type protein, presumably through the N-terminal regions of the protein which have been shown to be important for Vpr oligomerization. Thus, it is likely that complexation of the mutant Vpr with wild-type protein functionally inactivates Vpr. The importance of these findings in light of the development of therapeutic strategies is discussed.
Sawaya
B E
BE
Center for Neurovirology and Cancer Biology, Temple University, Philadelphia, Pennsylvania 19122, USA.
Khalili
K
K
Gordon
J
J
Srinivasan
A
A
Richardson
M
M
Rappaport
J
J
Amini
S
S
D001120:Arginine / Q000737:chemistry*; D001253:Astrocytes; D002453:Cell Cycle; D002478:Cells, Cultured; D016336:Gene Products, vpr / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016334:Genes, vpr; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009154:Mutation; D020079:Terminal Repeat Sequences / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection; D014779:Virus Replication; D054325:vpr Gene Products, Human Immunodeficiency Virus
D016336:Gene Products, vpr; D054325:vpr Gene Products, Human Immunodeficiency Virus; D001120:Arginine