Vif, one of the six accessory genes expressed by HIV-1, is essential for the productive infection of natural target cells. Previously we suggested that Vif acts as a regulator of the viral protease (PR): It prevents the autoprocessing of Gag and Gag-Pol precursors until virus assembly, and it may control the PR activity in the preintegration complex at the early stage of infection. It was demonstrated before that Vif, and specifically the 98 amino acid stretch residing at the N′-terminal part of Vif (N′-Vif), inhibits both the auto-processing of truncated Gag-Pol polyproteins in bacterial cells and the hydrolysis of synthetic peptides by PR in cell-free systems. Linear synthetic peptides derived from N′-Vif specifically inhibit and bind HIV-1 PR in vitro, and arrest virus production in tissue culture. Peptide mapping of N′-Vif revealed that Vif88-98 is the most potent PR inhibitor. Here we report that this peptide inhibits both HIV-1 and HIV-2, but not ASLV proteases in vitro. Vif88-98 retains its inhibitory effect against drug-resistant HIV-1 PR variants, isolated from patients undergoing long-term treatment with anti-PR drugs. Variants of HIV protease bearing the mutation G48V are resistant to inhibition by this Vif-derived peptide, as shown by in vitro assays. In agreement with the in vitro experiments, Vif88-98 has no effect on the production of infectious particles in cells infected with a G48V mutated virus.
|Number of pages
|Biochemical and Biophysical Research Communications
|Published - 2002
Bibliographical noteFunding Information:
This work was carried out in the Peter A. Krueger Laboratory with the generous support of Nancy and Lawrence Glick and Pat and Marvin Weiss. This work was supported by grants from the Israel Science Foundation, Israeli Ministry of Health, Israeli-Canadian Research Foundation (Ministry of Science, State of Israel) and from the Horowitz Investment Fund. We thank Roche Products Ltd. for the Ro31-8959, Ms. Josephine Silfen for peptide synthesis. We thank Drs. Lawrence Kuo and David Olsen, as well as Ms. Carrie Rut-kowsky, of the Department of Antiviral Research, Merck Research Laboratories, for measuring the inhibitory potency of our Vif pep- tides on HIV-1 protease variants that are resistant to a variety of protease inhibitors. HIV-2 PR was obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH.
- HIV protease