Small-molecule inhibition of HIV-1 Vif.
The HIV-1 protein Vif, essential for in vivo viral replication, targets the human DNA-editing enzyme, APOBEC3G (A3G), which inhibits replication of retroviruses and hepatitis B virus. 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 A3G, 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.
Nathans
Robin
R
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Cao
Hong
H
Sharova
Natalia
N
Ali
Akbar
A
Sharkey
Mark
M
Stranska
Ruzena
R
Stevenson
Mario
M
Rana
Tariq M
TM
D000071480:APOBEC-3G Deaminase; D019380:Anti-HIV Agents / Q000276:immunology / Q000627:therapeutic use*; D003564:Cytidine Deaminase / Q000235:genetics / Q000276:immunology*; D043525:Cytosine Deaminase / Q000037:antagonists & inhibitors* / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology* / Q000517:prevention & control*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
D019380:Anti-HIV Agents; D054320:vif Gene Products, Human Immunodeficiency Virus; D043525:Cytosine Deaminase; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human; D003564:Cytidine Deaminase