Title

Small-molecule inhibition of HIV-1 Vif

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Program in Molecular Medicine

Publication Date

9-23-2008

Document Type

Article

Subjects

Anti-HIV Agents; Cytidine Deaminase; Cytosine Deaminase; HIV Infections; HIV-1; Humans; Immunity, Innate; vif Gene Products, Human Immunodeficiency Virus

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

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.

Rights and Permissions

Citation: Nat Biotechnol. 2008 Oct;26(10):1187-92. Epub 2008 Sep 21. Link to article on publisher's site

DOI of Published Version

10.1038/nbt.1496

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Nature biotechnology

PubMed ID

18806783