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The effects of RNase H inhibitors and nevirapine on the susceptibility of HIV-1 to AZT and 3TC.

ABSTRACT: It was recently proposed that HIV RT mutations that decrease RNase H activity increase zidovudine (AZT) resistance by delaying the degradation of the RNA template, allowing more time for AZTMP excision from the 3' end of the viral DNA. This predicts that suboptimal concentrations of an RNase H Inhibitor (RNHI), which would decrease RNaseH activity, would decrease AZT susceptibility. Conversely, a suboptimal concentration of a nonnucleoside RT inhibitor (NNRTI) would decrease polymerase activity and increase AZT susceptibility. We determined the effect of several RNHIs and an NNRTI (nevirapine) on AZT and lamivudine (3TC) susceptibility with vectors that replicate using WT or AZT resistant RTs. Susceptibility to 3TC, which is not readily excised, did not change significantly. Nevirapine, and most RNHIs tested, had only small effects on the susceptibility of either HIV vector to AZT and 3TC. One RNHI, F0444-0019, increased the IC(50) for AZT for either vector by ~5-fold, which may be a concern.

SUBMITTER: Davis CA

PROVIDER: S-EPMC3262452 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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The effects of RNase H inhibitors and nevirapine on the susceptibility of HIV-1 to AZT and 3TC.

Davis Caroline A CA Parniak Michael A MA Hughes Stephen H SH

Virology 20110909 2

It was recently proposed that HIV RT mutations that decrease RNase H activity increase zidovudine (AZT) resistance by delaying the degradation of the RNA template, allowing more time for AZTMP excision from the 3' end of the viral DNA. This predicts that suboptimal concentrations of an RNase H Inhibitor (RNHI), which would decrease RNaseH activity, would decrease AZT susceptibility. Conversely, a suboptimal concentration of a nonnucleoside RT inhibitor (NNRTI) would decrease polymerase activity ...[more]

PMID: 21907380

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Project description:BackgroundDaily nevirapine (NVP) prophylaxis to HIV-exposed infants significantly reduces breast-milk HIV transmission. We assessed NVP-resistance in Indian infants enrolled in the "six-week extended-dose nevirapine" (SWEN) trial who received single-dose NVP (SD-NVP) or SWEN for prevention of breast-milk HIV transmission but who also acquired subtype C HIV infection during the first year of life.Methods/findingsStandard population sequencing and cloning for viral subpopulations present at > or =5% frequency were used to determine HIV genotypes from 94% of the 79 infected Indian infants studied. Timing of infection was defined based on when an infant's blood sample first tested positive for HIV DNA. SWEN-exposed infants diagnosed with HIV by six weeks of age had a significantly higher prevalence of NVP-resistance than those who received SD-NVP, by both standard population sequencing (92% of 12 vs. 38% of 29; p = 0.002) and low frequency clonal analysis (92% of 12 vs. 59% of 29; p = 0.06). Likelihood of infection with NVP-resistant HIV through breast-milk among infants infected after age six weeks was substantial, but prevalence of NVP-resistance did not differ among SWEN or SD-NVP exposed infants by standard population sequencing (15% of 13 vs. 15% of 20; p = 1.00) and clonal analysis (31% of 13 vs. 40% of 20; p = 0.72). Types of NVP-resistance mutations and patterns of persistence at one year of age were similar between the two groups. NVP-resistance mutations did differ by timing of HIV infection; the Y181C variant was predominant among infants diagnosed in the first six weeks of life, compared to Y188C/H during late breast-milk transmission.Conclusions/significanceUse of SWEN to prevent breast-milk HIV transmission carries a high likelihood of resistance if infection occurs in the first six weeks of life. Moreover, there was a continued risk of transmission of NVP-resistant HIV through breastfeeding during the first year of life, but did not differ between SD-NVP and SWEN groups. As with SD-NVP, the value of preventing HIV infection in a large number of infants should be considered alongside the high risk of resistance associated with extended NVP prophylaxis.Trial registrationClinicalTrials.gov NCT00061321.

Dataset Information

The effects of RNase H inhibitors and nevirapine on the susceptibility of HIV-1 to AZT and 3TC.

Publications

The effects of RNase H inhibitors and nevirapine on the susceptibility of HIV-1 to AZT and 3TC.

Similar Datasets

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