Small-molecule inhibition of HIV-1 Vif

Robin Nathans, Hong Cao, Natalia Sharova, Akbar Ali, Mark E Sharkey, Ruzena Stranska, Mario Stevenson, Tariq M. Rana

Research output: Contribution to journalArticle

143 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1187-1192
Number of pages6
JournalNature Biotechnology
Volume26
Issue number10
DOIs
StatePublished - Oct 1 2008
Externally publishedYes

Fingerprint

Viruses
Virion
HIV-1
Proteins
Degradation
Cytidine
Deamination
Molecules
Viral Genome
Proteasome Endopeptidase Complex
Retroviridae
Chelation
Innate Immunity
Hepatitis B virus
Proteolysis
HIV Infections
Antiviral Agents
Zinc
DNA
Enzymes

ASJC Scopus subject areas

  • Applied Microbiology and Biotechnology
  • Biotechnology
  • Molecular Medicine
  • Bioengineering
  • Biomedical Engineering

Cite this

Nathans, R., Cao, H., Sharova, N., Ali, A., Sharkey, M. E., Stranska, R., ... Rana, T. M. (2008). Small-molecule inhibition of HIV-1 Vif. Nature Biotechnology, 26(10), 1187-1192. https://doi.org/10.1038/nbt.1496

Small-molecule inhibition of HIV-1 Vif. / Nathans, Robin; Cao, Hong; Sharova, Natalia; Ali, Akbar; Sharkey, Mark E; Stranska, Ruzena; Stevenson, Mario; Rana, Tariq M.

In: Nature Biotechnology, Vol. 26, No. 10, 01.10.2008, p. 1187-1192.

Research output: Contribution to journalArticle

Nathans, R, Cao, H, Sharova, N, Ali, A, Sharkey, ME, Stranska, R, Stevenson, M & Rana, TM 2008, 'Small-molecule inhibition of HIV-1 Vif', Nature Biotechnology, vol. 26, no. 10, pp. 1187-1192. https://doi.org/10.1038/nbt.1496
Nathans R, Cao H, Sharova N, Ali A, Sharkey ME, Stranska R et al. Small-molecule inhibition of HIV-1 Vif. Nature Biotechnology. 2008 Oct 1;26(10):1187-1192. https://doi.org/10.1038/nbt.1496
Nathans, Robin ; Cao, Hong ; Sharova, Natalia ; Ali, Akbar ; Sharkey, Mark E ; Stranska, Ruzena ; Stevenson, Mario ; Rana, Tariq M. / Small-molecule inhibition of HIV-1 Vif. In: Nature Biotechnology. 2008 ; Vol. 26, No. 10. pp. 1187-1192.
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