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首页> 外文期刊>JAIDS: Journal of acquired immune deficiency syndromes >HIV-1 reverse transcriptase mutants resistant to nonnucleoside reverse transcriptase inhibitors do not adversely affect DNA synthesis: pre-steady-state and steady-state kinetic studies.
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HIV-1 reverse transcriptase mutants resistant to nonnucleoside reverse transcriptase inhibitors do not adversely affect DNA synthesis: pre-steady-state and steady-state kinetic studies.

机译：对非核苷类逆转录酶抑制剂具有抗性的HIV-1逆转录酶突变体不会对DNA合成产生不利影响：稳态前和稳态动力学研究。

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摘要

We have previously demonstrated that nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant mutants have different levels of replication fitness relative to wild type; those with greater reductions in fitness are less likely to develop during therapy in patients. We have also found that reductions in rates of RNase H cleavage by mutant RTs correlate with reductions in fitness and that NNRTI-resistant RTs catalyze polymerization with a processivity similar to wild type. In this study, we evaluated the polymerase function of 3 clinically occurring NNRTI-resistant RTs (K103N, P236L, and V106A) in greater detail, under both pre-steady-state and steady-state conditions. The overall pathway of single-nucleotide incorporation was unchanged for the mutant RTs compared with wild type. In addition, the NNRTI-resistant mutants were each similar to wild type in rate of nucleotide incorporation (kpol), affinity for dGTP (Kd), and steady-state rate of polymerization (kss and kcat), using either RNA or DNA templates. These findings suggest that the close proximity of the NNRTI-resistance mutations to the polymerase active site does not affect the interactions of the enzyme with the incoming nucleotide or the primer-template sufficiently to affect polymerization and support the hypothesis that these reductions in RNase H activity contribute to reductions in replication fitness.
机译：先前我们已经证明，相对于野生型，非核苷类逆转录酶抑制剂（NNRTI）耐药突变体具有不同水平的复制适应性。那些身体健康状况下降幅度较大的患者，在治疗期间不太可能出现。我们还发现，突变体RTs切割RNase H的速率降低与适应性降低相关，并且耐NNRTI的RTs催化聚合反应的合成能力类似于野生型。在这项研究中，我们在稳态之前和稳态条件下，更详细地评估了3种临床上发生的NNRTI耐药RTs（K103N，P236L和V106A）的聚合酶功能。与野生型相比，突变体RT的单核苷酸掺入的总途径没有改变。此外，使用RNA或DNA模板，抗NNRTI的突变体在核苷酸掺入率（kpol），对dGTP的亲和力（Kd）和稳态聚合率（kss和kcat）方面均类似于野生型。这些发现表明，NNRTI抗性突变与聚合酶活性位点的紧密接近不会充分影响酶与传入核苷酸或引物模板的相互作用，从而不会影响聚合反应并支持以下假设：RNase H活性的这些降低有助于降低复制适应性。

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