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Small-molecule inhibition of HIV-1 Vif

Abstract

The HIV-1 protein Vif, essential for in vivo viral replication1,2,3,4, targets the human DNA-editing enzyme, APOBEC3G (A3G)5, which inhibits replication of retroviruses and hepatitis B virus6,7. As Vif has no known cellular homologs, it is an attractive, yet unrealized, target for antiviral intervention. Although zinc chelation inhibits Vif and enhances viral sensitivity to A3G8, this effect is unrelated to the interaction of Vif with A3G. We identify a small molecule, RN-18, that antagonizes Vif function and inhibits HIV-1 replication only in the presence of A3G. RN-18 increases cellular A3G levels in a Vif-dependent manner and increases A3G incorporation into virions without inhibiting general proteasome-mediated protein degradation. RN-18 enhances Vif degradation only in the presence of A3G, reduces viral infectivity by increasing A3G incorporation into virions and enhances cytidine deamination of the viral genome. These results demonstrate that the HIV-1 Vif-A3G axis is a valid target for developing small molecule–based new therapies for HIV infection or for enhancing innate immunity against viruses.

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Figure 1: Small molecules that inhibit HIV-1 Vif.
Figure 2: The small-molecule Vif antagonist, RN-18, inhibits HIV-1 replication in nonpermissive cells but not in permissive cells.
Figure 3: The Vif antagonist, RN-18, increases APOBEC3G abundance in HIV-1 producer cells and virions, but does not affect APOBEC3B levels.
Figure 4: The Vif antagonist, RN-18, enhances APOBEC3G expression in nonpermissive cells and in a Vif-dependent manner.

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Acknowledgements

The HIV-1 subgenomic proviral vector pNL-A1 harboring HXB2 strain Vif, and the corresponding pNL-A1Δvif were generous gifts of Klaus Strebel. HIV-1 luciferase reporter constructs pNL4-3LucRE and pNL4-3ΔVif LucRE were provided by Nathaniel Landau through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH. The plasmid APOBEC3F-HA was a gift from Michael Malim, and plasmids APOBEC3B-HA and APOBEC3C-HA were generous gifts from Bryan Cullen. We also thank Rana laboratory members for helpful discussions and support and the University of Massachusetts Center for AIDS Research (CFAR) for virology support. This work was supported in part by an NIH grant to T.M.R. and M.S. and by a Developmental award from the UMASS CFAR.

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Correspondence to Mario Stevenson or Tariq M Rana.

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Nathans, R., Cao, H., Sharova, N. et al. Small-molecule inhibition of HIV-1 Vif. Nat Biotechnol 26, 1187–1192 (2008). https://doi.org/10.1038/nbt.1496

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