AIDSWEEKLY Plus; Monday, November 23, 1998
Daniel J. DeNoon, Senior Editor
Columbia University researchers Mary Jane Potash, David J. Volsky, and colleagues have found that the HIV virion infectivity factor (the Vif protein) inhibits HIV protease during the normal life cycle of the virus.
They suggest that HIV mutants that are resistant to Vif-based protease inhibitors may not be able to remain viable, since the virus appears to require Vif-associated protease inhibition during a crucial stage of development.
"The Vif peptides described here preserve the endogenous protease inhibitory capacity of the intact protein and may be useful for the development of new inhibitors of HIV-1 infection," Potash et al. wrote. "Because HIV-1 has evolved to conserve the Vif/protease interaction, mutants in protease resistant to Vif-based antiviral agents may be less frequent than protease mutants resistant to existing inhibitors."
Potash et al. reported their findings in the journal Proceedings of the National Academy of Sciences ("Peptide Inhibitors of HIV-1 Protease and Viral Infection of Peripheral Blood Lymphocytes Based on HIV-1 Vif," PNAS, 1998;95:13865-8).
Although once considered a minor regulatory protein, Vif is now known to be essential for productive HIV infection of lymphocyte and macrophage cultures. In animal models of AIDS Vif is required for pathogenesis.
"The predominant view is that Vif acts at the late stages of infection to promote virion processing or assembly," Potash et al. noted.
The researchers earlier found that Vif prevents HIV protease from slicing up viral precursor proteins until the proper time for assembly of viral particles (Simm, M. et al., J Virol, 1995;69:4582-6). In their current studies they have synthesized peptide derivatives from the region of the Vif protein responsible for protease inhibition.
The Vif peptide comprising residues 21-65 (Vif[21-65]) and a smaller peptide, Vif[41-65], inhibited in vitro HIV expression below the limits of detection. These results were similar to those seen with saquinavir, an approved HIV protease inhibitor currently used in some highly active antiretroviral therapy (HAART) regimens.
"Vif-derived peptides offer an avenue for the development of novel protease inhibitors that use endogenous HIV-1 functions for the treatment of HIV-1 infection," Potash et al. concluded.
This work was supported by National Institutes of Health grants and by a Pew Charitable Trust scholarship.
The corresponding author for this study is David J. Volsky, Molecular Virology Laboratory, St. Luke's-Roosevelt Hospital Center, Columbia University, New York, New York 10019. Email: <djv4@columbia.edu>.
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