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J Virol. 2012 May;86(10):5885-94. doi: 10.1128/JVI.06597-11. Epub 2012 Mar 21.

HIV-1 and HIV-2 reverse transcriptases: different mechanisms of resistance to nucleoside reverse transcriptase inhibitors.

Author information

1
HIV Drug Resistance Program, National Cancer Institute-Frederick, National Institutes of Health, Frederick, Maryland, USA.

Abstract

As anti-HIV therapy becomes more widely available in developing nations, it is clear that drug resistance will continue to be a major problem. The related viruses HIV-1 and HIV-2 share many of the same resistance pathways to nucleoside reverse transcriptase inhibitors (NRTIs). However, clinical data suggest that while HIV-1 reverse transcriptase (RT) usually uses an ATP-dependent excision pathway to develop resistance to the nucleoside analog zidovudine (AZT), HIV-2 RT does not appear to use this pathway. We previously described data that suggested that wild-type (WT) HIV-2 RT has a much lower ability to excise AZT monophosphate (AZTMP) than does WT HIV-1 RT and suggested that this is the reason that HIV-2 RT more readily adopts an exclusion pathway against AZT triphosphate (AZTTP), while HIV-1 RT is better able to exploit the ATP-dependent pyrophosphorolysis mechanism. However, we have now done additional experiments, which show that while HIV-1 RT can adopt either an exclusion- or excision-based resistance mechanism against AZT, HIV-2 RT can use only the exclusion mechanism. All of our attempts to make HIV-2 RT excision competent did not produce an AZT-resistant RT but instead yielded RTs that were less able to polymerize than the WT. This suggests that the exclusion pathway is the only pathway available to HIV-2.

PMID:
22438533
PMCID:
PMC3347278
DOI:
10.1128/JVI.06597-11
[Indexed for MEDLINE]
Free PMC Article

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