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Biochemical, inhibition and inhibitor resistance studies of xenotropic murine leukemia virus-related virus reverse transcriptase. 2012
Tanyaradzwa P Ndongwe, and
Adeyemi O Adedeji, and
Eleftherios Michailidis, and
Yee Tsuey Ong, and
Atsuko Hachiya, and
Bruno Marchand, and
Emily M Ryan, and
Devendra K Rai, and
Karen A Kirby, and
Angela S Whatley, and
Donald H Burke, and
Marc Johnson, and
Shilei Ding, and
Yi-Min Zheng, and
Shan-Lu Liu, and
Ei-Ichi Kodama, and
Krista A Delviks-Frankenberry, and
Vinay K Pathak, and
Hiroaki Mitsuya, and
Michael A Parniak, and
Kamalendra Singh, and
Stefan G Sarafianos
Christopher Bond Life Sciences Center, Department of Molecular Microbiology & Immunology, University of Missouri, School of Medicine, Columbia, MO 65211, USA.
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 (k(off)) 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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