Mutational Patterns in the HIV Genome and Cross-Resistance following Nucleoside and Nucleotide Analogue Drug Exposure

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Abstract
A variety of key mutations in HIV reverse transcriptase (RT) have been associated with nucleoside reverse transcriptase inhibitor (NRTI) exposure, which give rise to a diverse range of effects in terms of altered drug susceptibilities, viral replicative capacity and RT biochemistry. There are three basic mechanisms of resistance conferred by specific mutations in the coding region of RT. The first is drug discrimination, whereby a particular drug or drugs are either selectively excluded from uptake or from the RT–primer–template catalytic complex. Drug discrimination is, for the most part, relatively specific for individual drugs. Repositioning of the template–primer to prevent a catalytically competent complex in the presence of a bound drug molecule has also been observed in some instances, and forms a second mechanism. The third, and potentially most significant for long-term efficacy of the NRTIs, is pyrophosphorolysis, the primary mode of resistance to zidovudine. Mutations selected by this drug or stavudine serve to elevate the natural rate of the reverse reaction for RT. Pyrophosphorolysis uncouples the last nucleoside monophosphate added to the proviral transcript, and attaches it to either a free pyrophosphate (regenerating a deoxynucleoside triphosphate) or to a nucleoside di- or triphosphate (usually ATP). Uncoupling a chain-terminating NRTI residue therefore rescues reverse transcription and reduces drug susceptibility across the class, since the process is not specific for the selecting drug. Of all the nucleoside-associated mutations, the best known and most studied are the six associated with thymidine analogue exposure. These six mutations (M41L, D67N, K70R, L210W, T215Y/F, K219Q) enhance RT pyrophosphorolysis to confer high-level viral resistance to zidovudine, and clinically significant loss of response to stavudine and didanosine. They have also been found to confer reduced susceptibility to lamivudine and abacavir, particularly when present alongside other NRTI-induced changes. Other key mutations generally confer more limited resistance to specific agents, although the primary lamivudine- and abacavir-associated M184V substitution generates a broad spectrum of drug-dependent phenotypes, and uncommon mutational complexes conferring resistance across the entire class are well known. In addition to ‘classical’ multi-nucleoside-resistant genotypes, database-driven ‘virtual phenotyping’ for accumulations of NRTI-associated mutations around a core of thymidine analogue-induced changes predicts drug susceptibilities below wild-type across the entire NRTI class, even in the absence of key mutations associated with individual agents. When the natural range of drug susceptibilities for treatment-naive isolates is used as the basis for defining resistance, retrospective analysis of clinical isolates in the Virco database shows a significantly increased incidence of reduced susceptibility for the dideoxy NRTIs (didanosine, stavudine and zalcitabine) that was undetected in previous assays. These data imply a cumulative degradation of response to NRTI drugs incident on the failure of thymidine analogue-based combinations, consistent with observations of treatment-experienced versus treatment-naive individuals. Among the investigational agents, response to tenofovir disproxil fumarate (TDF) appears to be essentially independent of baseline genotype in NRTI-experienced individuals, and its sole selected resistance mutation, K65R, has been observed to emerge only rarely (2%) and without loss of clinical response. In vitro results also show very little effect on TDF susceptibility for the most common of the multi-nucleoside resistance patterns. This drug has also been shown to display a substantially reduced sensitivity to pyrophosphorolytic uncoupling in vitro, which may, in part, explain the surprisingly sustained response observed over 48 weeks for TDF intensification of an existing regimen.

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