Biochemical, inhibition and inhibitor resistance studies of xenotropic murine leukemia virus-related virus reverse transcriptase.
Biochemical, inhibition and inhibitor resistance studies of xenotropic murine leukemia virus-related virus reverse transcriptase.
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DOI：
10.1093/nar/gkr694
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发表时间：
2012-01
影响因子：
14.9
通讯作者：
Sarafianos SG
中科院分区：
文献类型：
--
作者：
Ndongwe TP;Adedeji AO;Michailidis E;Ong YT;Hachiya A;Marchand B;Ryan EM;Rai DK;Kirby KA;Whatley AS;Burke DH;Johnson M;Ding S;Zheng YM;Liu SL;Kodama E;Delviks-Frankenberry KA;Pathak VK;Mitsuya H;Parniak MA;Singh K;Sarafianos SG
我们报告了人类免疫缺陷病毒1型（HIV-1）和异嗜性小鼠白血病病毒相关病毒（XMRV）的逆转录酶（RT）之间的关键机制差异，XMRV是一种可以感染人类细胞的γ -逆转录病毒。稳态和预稳态动力学表明，XMRV RT在DNA合成和解封链端引物中的效率明显较低。表面等离子体共振实验表明，γ -逆转录病毒酶与DNA的解离率（koff）显著更高，这也导致了比HIV-1 RT更低的加工速度。失配结合的瞬态动力学表明，XMRV RT比HIV-1 RT具有更高的保真度。我们鉴定了RNA适体，这些适体可以有效抑制XMRV，但HIV-1 RT没有。但对非核苷类RT抑制剂没有作用。我们证明XMRV RT突变体K103R和Q190M，相当于HIV-1对替诺福韦（K65R）和AZT （Q151M）耐药的突变体，也对各自的药物耐药，这表明XMRV可以通过HIV-1中报道的减少掺入机制获得对这些化合物的耐药性。
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.
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影响因子：
3.7
作者：
Erlwein O;Kaye S;McClure MO;Weber J;Wills G;Collier D;Wessely S;Cleare A
通讯作者：
Cleare A
影响因子：
3.3
作者：
Groom HC;Boucherit VC;Makinson K;Randal E;Baptista S;Hagan S;Gow JW;Mattes FM;Breuer J;Kerr JR;Stoye JP;Bishop KN
通讯作者：
Bishop KN
影响因子：
2.9
作者：
CHEN, H;GOLD, L
通讯作者：
GOLD, L
DOI：
10.1073/pnas.90.13.6320
发表时间：
1993-07-01
影响因子：
11.1
作者：
JACOBOMOLINA, A;DING, JP;ARNOLD, E
通讯作者：
ARNOLD, E
影响因子：
2.1
作者：
Arnold, Rebecca S.;Makarova, Natalia V.;Petros, John A.
通讯作者：
Petros, John A.