AEGiS-12IAC: Cell cycle G2 arrest by HIV-1 Vpr is not responsible for Vpr-induced cell death.

12th International AIDS Conference

Geneva, Switzerland - June 28-July 3, 1998

Cell cycle G2 arrest by HIV-1 Vpr is not responsible for Vpr-induced cell death.

Int Conf AIDS 1998 Jun 28-Jul 3; 12:10 (abstract no. 11141)

Zhao Y, Elder RT, Yu M, Chen MZ
North Western Univ. Med. School, Chicago, IL, USA.

BACKGROUND: HIV-1 Vpr plays an important role in pathogenesis as it activates viral replication and is involved in the depletion of CD4+ T lymphocytes. Expression of the HIV-1 vpr gene induces cell cycle G2 arrest and cell death in both human and fission yeast cells. The target for Vpr-induced cell cycle G2 arrest is the cyclin dependent kinase p34cdc2 whose activation requires dephosphorylation, a process that determines the onset of mitosis in all eukaryotic cells. Vpr induces G2 arrest by preventing dephosphorylation of p34cdc2. HYPOTHESIS: Vpr-induced cell death is the result of cell cycle G2 arrest

METHODS: Genetic and biochemical methods were used to characterize G2 arrest and cell death in fission yeast cells, in which the highly conserved cell cycle controls are well characterized.

RESULTS: Consistent with Vpr affecting the phosphorylation state of p34cdc2 to induce G2 arrest, gene mutations that affect phosphorylation in p34cdc2 either abolished (in cdc2-L7 mutant strain) or severely reduced (in cdc2-1w and cdc2-3w mutant strains) the ability of Vpr to induce G2 arrest. Our studies further suggest that the inhibitory effect of Vpr on p34cdc2 is mediated through the well characterized inhibitory phosphorylation site on tyrosine 15 (Tyr 15) of p34cdc2. Substitution of phenylalanine for tyrosine (Y15F) prevents phosphorylation on Tyr15 and completely abolishes the ability of Vpr to induce G2 arrest. Interestingly, this Y15F mutation was unable to abrogate Vpr-induced cell death suggesting that cell death is independent of G2 arrest. This conclusion was further supported by our finding that a point mutation in vpr that results in a replacement of histidine with arginine at amino acid 78 (H78R), ameliorated cell death induced by Vpr while maintaining its ability to induce G2 arrest.

CONCLUSIONS: Induction of cell cycle G2 arrest and cellular death are independent functions of HIV-1 Vpr.

Keywords: AEGIS, Genes, vpr, Cell Death, HIV-1, Schizosaccharomyces, Mitosis, Phosphorylation, Schizosaccharomyces pombe Proteins, Tyrosine, Mutation, Human, genetics, ICA12
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