Roquebert Bénédicte, Marcelin Anne-Geneviève
AP-HP, Groupe Hospitalier Bichat-Claude Bernard, Service de Virologie, Paris F-75018, France.
J Antimicrob Chemother. 2008 May;61(5):973-5. doi: 10.1093/jac/dkn060. Epub 2008 Mar 5.
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.
最近的一些研究强调了整个逆转录酶（RT）的作用，特别是其从氨基酸427到氨基酸560的羧基末端结构域[核糖核酸酶H（RNAse H）结构域]在对核苷类逆转录酶抑制剂（NRTIs）耐药性中的作用。RNAse H参与催化病毒基因组转化为双链DNA过程中RNA链的降解。通过定点诱变已表明，RNAse H结构域中的氨基酸取代可能会影响酶与底物的结合，导致RNAse H活性降低。例如，478、539和549位的突变导致RNA链降解减缓。在体外，H539N和D549N突变降低了RT模板转换的频率，从而增加了掺入的NRTIs切除的时间，进而增强了对NRTIs的耐药性。在一项纳入144例HIV-1患者的研究中，体内已证实558位的突变与多个胸苷类似物突变在统计学上相关，这表明它可能是一个辅助突变，可增强对NRTIs的耐药性。本文强调了RNAse H中的突变可增强对NRTIs耐药性的证据，这表明现在需要对包括整个HIV-1 RT特别是RNAse H结构域的临床样本进行表型和基因型分析，以更好地描述RNAse H突变在HIV-1感染患者中对NRTIs敏感性和反应的体内作用。
