The involvement of HIV-1 RNAse H in resistance to nucleoside analogues.
Some recent studies have underlined the role of the entire reverse transcriptase (RT) and in particular its carboxy-terminal domain from amino acid 427 to amino acid 560 [the ribonuclease H (RNAse H) domain] in resistance to nucleoside RT inhibitors (NRTIs). RNAse H is implicated in catalysing the degradation of the RNA strand during conversion of the viral genome into double-stranded DNA. It has been shown, by site-directed mutagenesis, that amino acid substitutions in the RNAse H domain could affect the binding enzyme/substrate, resulting in a decrease in the RNAse H activity. For example, mutations at positions 478, 539 and 549 led to a slowing down in the degradation of the RNA strand. In vitro, the mutations H539N and D549N decreased the frequency of RT template-switching and, thereby, increased the time for excision of incorporated NRTIs, and thus enhanced NRTI resistance. It has been confirmed in vivo that mutations at position 558 were statistically associated with a number of thymidine analogue mutations in a study including 144 HIV-1 patients, suggesting that it could be an accessory mutation that could reinforce NRTI resistance. This article highlights evidence that mutations in RNAse H can enhance NRTI resistance, suggesting that phenotypic and genotypic analyses of clinical samples including the entire HIV-1 RT and in particular the RNAse H domain are now required to better characterize the in vivo role of the RNAse H mutations on susceptibility and response to NRTIs in HIV-1-infected patients.
Roquebert
Bénédicte
B
AP-HP, Groupe Hospitalier Bichat-Claude Bernard, Service de Virologie, Paris F-75018, France.
Marcelin
Anne-Geneviève
AG
D019380:Anti-HIV Agents / Q000494:pharmacology*; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology*; D009154:Mutation; D012194:RNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D016914:Ribonuclease H / Q000235:genetics* / Q000378:metabolism*
D019380:Anti-HIV Agents; D012194:RNA-Directed DNA Polymerase; D016914:Ribonuclease H