Journal
CELL HOST & MICROBE
Volume 4, Issue 3, Pages 260-270Publisher
CELL PRESS
DOI: 10.1016/j.chom.2008.07.008
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Funding
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH
- National Cancer Institute, NIH [NO1-CO-12400]
- NIH [5P30-AI-50409 (CFAR), 5R37-AI-041980]
- Geconcerteerde Onderzoeksacties [05/19]
- Canadian Institutes of Health Research
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For most viruses, there is a need for antimicrobials that target unique viral molecular properties. Acyclovir (ACV) is one such drug. It is activated into a human herpesvirus (HHV) DNA polymerase inhibitor exclusively by HHV kinases and, thus, does not suppress other viruses. Here, we show that ACV suppresses HIV-1 in HHV-coinfected human tissues, but not in HHV-free tissue or cell cultures. However, addition of HHV-6-infected cells renders these cultures sensitive to anti-HIV ACV activity. We hypothesized that such HIV suppression requires ACV phosphorylation by HHV kinases. Indeed, an ACV monophosphorylated prodrug bypasses the HHV requirement for HIV suppression. Furthermore, phosphorylated ACV directly inhibits HIV-1 reverse transcriptase (RT), terminating DNA chain elongation, and can trap RT at the termination site. These data suggest that ACV anti-HIV-1 activity may contribute to the response of HIV/HHV-coinfected patients to ACV treatment and could guide strategies for the development of new HIV-1 FIT inhibitors.
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