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 language | English |
|---|---|
| Pages (from-to) | 1187-1192 |
| Number of pages | 6 |
| Journal | Nature Biotechnology |
| Volume | 26 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 1 2008 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Applied Microbiology and Biotechnology
- Biotechnology
- Molecular Medicine
- Bioengineering
- Biomedical Engineering
Cite this
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 journal › Article
}
TY - JOUR
T1 - Small-molecule inhibition of HIV-1 Vif
AU - Nathans, Robin
AU - Cao, Hong
AU - Sharova, Natalia
AU - Ali, Akbar
AU - Sharkey, Mark E
AU - Stranska, Ruzena
AU - Stevenson, Mario
AU - Rana, Tariq M.
PY - 2008/10/1
Y1 - 2008/10/1
N2 - 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.
AB - 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.
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U2 - 10.1038/nbt.1496
DO - 10.1038/nbt.1496
M3 - Article
C2 - 18806783
AN - SCOPUS:53649086178
VL - 26
SP - 1187
EP - 1192
JO - Nature Biotechnology
JF - Nature Biotechnology
SN - 1087-0156
IS - 10
ER -