title: HIV-1 and HIV-2 reverse transcriptases: different mechanisms of resistance to nucleoside reverse transcriptase inhibitors.
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.
authors.affiliation: HIV Drug Resistance Program, National Cancer Institute-Frederick, National Institutes of Health, Frederick, Maryland, USA.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Boyer
authors.forename: Patrick K
authors.initials: PK
authors.lastname: Clark
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Hughes
mesh_terms: D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D015498:HIV-2 / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D015215:Zidovudine / Q000378:metabolism / Q000494:pharmacology
chemical_list: D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; C514824:reverse transcriptase, Human immunodeficiency virus 1; C072416:reverse transcriptase, Human immunodeficiency virus 2; D054303:HIV Reverse Transcriptase