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Biochemical, inhibition and inhibitor resistance studies of xenotropic murine leukemia virus-related virus reverse transcriptase

机译:异种鼠白血病病毒相关病毒逆转录酶的生化,抑制和抗药性研究

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摘要

We report key mechanistic differences between the reverse transcriptases (RT) of human immunodeficiency virus type-1 (HIV-1) and of xenotropic murine leukemia virus-related virus (XMRV), a gammaretrovirus that can infect human cells. Steady and pre-steady state kinetics demonstrated that XMRV RT is significantly less efficient in DNA synthesis and in unblocking chain-terminated primers. Surface plasmon resonance experiments showed that the gammaretroviral enzyme has a remarkably higher dissociation rate (koff) from DNA, which also results in lower processivity than HIV-1 RT. Transient kinetics of mismatch incorporation revealed that XMRV RT has higher fidelity than HIV-1 RT. We identified RNA aptamers that potently inhibit XMRV, but not HIV-1 RT. XMRV RT is highly susceptible to some nucleoside RT inhibitors, including Translocation Deficient RT inhibitors, but not to non-nucleoside RT inhibitors. We demonstrated that XMRV RT mutants K103R and Q190M, which are equivalent to HIV-1 mutants that are resistant to tenofovir (K65R) and AZT (Q151M), are also resistant to the respective drugs, suggesting that XMRV can acquire resistance to these compounds through the decreased incorporation mechanism reported in HIV-1.
机译:我们报告人类免疫缺陷病毒1型(HIV-1)和异种鼠白血病病毒相关病毒(XMRV),一种可以感染人类细胞的γ逆转录病毒的逆转录酶(RT)之间的关键机制差异。稳态和稳态前动力学表明XMRV RT在DNA合成和未封闭链终止引物中的效率明显较低。表面等离振子共振实验表明,γ-逆转录病毒酶与DNA的解离速率(koff)显着较高,这也导致其合成能力低于HIV-1 RT。错配掺入的瞬态动力学表明,XMRV RT具有比HIV-1 RT高的保真度。我们确定了RNA适体,可以有效抑制XMRV,但不能抑制HIV-1 RT。 XMRV RT对某些核苷RT抑制剂(包括易位缺陷RT抑制剂)高度敏感,但对非核苷RT抑制剂则不敏感。我们证明了XMRV RT突变体K103R和Q190M与耐替诺福韦(K65R)和AZT(Q151M)的HIV-1突变体相同,也对各自的药物具有耐药性,这表明XMRV可以通过以下途径获得对这些化合物的耐药性HIV-1中报道的掺入机制降低。

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