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

Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE

Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.

HIV Reverse Transcriptase/*chemistry ; HIV Reverse Transcriptase/*metabolism ; RNA-Directed DNA Polymerase/*chemistry ; RNA-Directed DNA Polymerase/*metabolism ; Xenotropic murine leukemia virus-related virus/*enzymology; Adenine/analogs & derivatives ; Adenine/pharmacology ; Amino Acid Sequence ; Aptamers, Nucleotide/pharmacology ; DNA/biosynthesis ; DNA/metabolism ; HIV Reverse Transcriptase/genetics ; Kinetics ; Models, Molecular ; Molecular Sequence Data ; Moloney murine leukemia virus/enzymology ; Mutation ; Nucleotides/metabolism ; Organophosphonates/pharmacology ; RNA-Directed DNA Polymerase/genetics ; Reverse Transcriptase Inhibitors/pharmacology ; Sequence Homology, Amino Acid ; Tenofovir ; Zidovudine/pharmacology ; beta-Galactosidase/genetics

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.

J Biol Chem. 1997 May 16;272(20):13262-9. (PMID: 9148945)
Science. 2011 Jul 1;333(6038):97-101. (PMID: 21628392)
AIDS Res Hum Retroviruses. 2007 May;23(5):699-708. (PMID: 17530996)
PLoS One. 2010 Jan 06;5(1):e8519. (PMID: 20066031)
Retrovirology. 2010 Dec 20;7:109. (PMID: 21171973)
Antimicrob Agents Chemother. 1994 Feb;38(2):275-81. (PMID: 7514855)
Protein Eng. 2000 Sep;13(9):635-43. (PMID: 11054458)
J Infect Dis. 2010 Nov 15;202(10):1478-81. (PMID: 20936980)
Chem Biol. 1999 May;6(5):R137-46. (PMID: 10322129)
Retrovirology. 2010 Feb 15;7:10. (PMID: 20156349)
Mol Cell Probes. 2011 Apr-Jun;25(2-3):134-6. (PMID: 21281710)
Biochemistry. 1996 Dec 24;35(51):16610-20. (PMID: 8987996)
Biochemistry. 2002 Dec 17;41(50):14831-42. (PMID: 12475231)
Biochemistry. 1994 Jul 26;33(29):8746-56. (PMID: 7518691)
PLoS One. 2010 Apr 01;5(4):e9948. (PMID: 20376347)
Curr Opin Struct Biol. 2004 Dec;14(6):716-30. (PMID: 15582396)
Science. 1998 Nov 27;282(5394):1669-75. (PMID: 9831551)
J Biol Chem. 2009 Dec 11;284(50):35092-100. (PMID: 19812032)
Structure. 2004 May;12(5):819-29. (PMID: 15130474)
PLoS One. 2011 Jan 13;6(1):e16242. (PMID: 21249155)
Retrovirology. 2010 Aug 31;7:70. (PMID: 20807431)
Annu Rev Biochem. 1993;62:685-713. (PMID: 7688945)
Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):2398-402. (PMID: 7534421)
J Biol Chem. 2009 Dec 18;284(51):35681-91. (PMID: 19837673)
EMBO J. 1993 Nov;12(11):4433-8. (PMID: 7693456)
Antimicrob Agents Chemother. 1993 Oct;37(10):2231-4. (PMID: 7504909)
Retrovirology. 2010 Dec 20;7:108. (PMID: 21171966)
J Biol Chem. 1995 Aug 25;270(34):19729-35. (PMID: 7544345)
Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16351-6. (PMID: 19805305)
Int J Biochem Cell Biol. 2004 Sep;36(9):1716-34. (PMID: 15183340)
Urology. 2010 Apr;75(4):755-61. (PMID: 20371060)
Mol Cell. 1999 Jul;4(1):35-43. (PMID: 10445025)
Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10027-32. (PMID: 10468556)
Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6320-4. (PMID: 7687065)
PLoS Pathog. 2006 Feb;2(2):e10. (PMID: 16485036)
Viruses. 2010 Feb 11;2(2):606-638. (PMID: 20376302)
Retrovirology. 2009 Oct 16;6:92. (PMID: 19835577)
Nat Struct Mol Biol. 2004 May;11(5):469-74. (PMID: 15107837)
J Virol. 2010 Jun;84(11):5719-29. (PMID: 20335265)
Nucleic Acids Res. 2006 Jan 05;34(1):130-9. (PMID: 16397296)
Science. 2009 Oct 23;326(5952):530-1. (PMID: 19815721)
PLoS Pathog. 2006 Mar;2(3):e25. (PMID: 16609730)
Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1276-80. (PMID: 7679498)
Retrovirology. 2011 Feb 22;8:12. (PMID: 21342521)
Int J Biochem Cell Biol. 2008;40(11):2410-20. (PMID: 18487070)
J Virol. 2000 Apr;74(8):3579-85. (PMID: 10729133)
Science. 1996 Mar 1;271(5253):1282-5. (PMID: 8638110)
Biochemistry. 1996 Feb 20;35(7):2168-79. (PMID: 8652558)
Nucleic Acids Res. 2008 Sep;36(15):5083-92. (PMID: 18676450)
Retrovirology. 2010 Dec 20;7:110. (PMID: 21171978)
Biochemistry. 2000 May 2;39(17):5155-65. (PMID: 10819983)
Structure. 1995 Sep 15;3(9):879-92. (PMID: 8535782)
EMBO J. 2001 Mar 15;20(6):1449-61. (PMID: 11250910)
Retrovirology. 2010 Jul 01;7:57. (PMID: 20594299)
Science. 2011 Jul 1;333(6038):94-7. (PMID: 21628393)
Proc Natl Acad Sci U S A. 2007 Jan 30;104(5):1655-60. (PMID: 17234809)
J Infect Dis. 1994 Apr;169(4):722-9. (PMID: 8133086)
Science. 1992 Jun 26;256(5065):1783-90. (PMID: 1377403)
Rev Med Virol. 2011 Jan;21(1):3-17. (PMID: 21294212)
J Virol. 1996 Feb;70(2):1086-90. (PMID: 8551567)
J Mol Biol. 2009 Jan 23;385(3):693-713. (PMID: 19022262)
Antiviral Res. 2010 Jan;85(1):210-31. (PMID: 19616029)
J Biol Chem. 1995 Oct 6;270(40):23605-11. (PMID: 7559526)
Int J Biochem Cell Biol. 2004 Sep;36(9):1706-15. (PMID: 15183339)
Curr Drug Targets Infect Disord. 2003 Dec;3(4):383-400. (PMID: 14754437)
Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13471-6. (PMID: 9811824)
Retrovirology. 2010 Dec 20;7(1):111. (PMID: 21171979)
Biochemistry. 1998 Nov 10;37(45):15908-17. (PMID: 9843396)
EMBO J. 2002 Dec 2;21(23):6614-24. (PMID: 12456667)
Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5653-6. (PMID: 7685907)
Science. 2009 Oct 23;326(5952):585-9. (PMID: 19815723)
Antimicrob Agents Chemother. 1997 Apr;41(4):757-62. (PMID: 9087484)
Virus Res. 2008 Jun;134(1-2):1-3. (PMID: 18299161)
Prostate. 2011 Mar 1;71(4):415-20. (PMID: 20878949)
J Virol. 2009 Jul;83(14):7353-6. (PMID: 19403664)
Virology. 2010 Feb 5;397(1):1-6. (PMID: 19959199)
J Biol Chem. 2010 Dec 3;285(49):38700-9. (PMID: 20876531)
Antimicrob Agents Chemother. 2001 May;45(5):1539-46. (PMID: 11302824)
Nature. 2007 Aug 16;448(7155):816-9. (PMID: 17653195)
Nucleic Acids Res. 2003 Jan 1;31(1):298-303. (PMID: 12520007)
J Virol. 2000 Jan;74(1):312-9. (PMID: 10590119)
Oligonucleotides. 2008 Jun;18(2):133-44. (PMID: 18637731)
Biochemistry. 1991 Jan 15;30(2):511-25. (PMID: 1846298)
Cell Mol Biol (Noisy-le-grand). 2011 Feb 12;57(1):40-6. (PMID: 21366961)

AI079801 United States AI NIAID NIH HHS; AI076119 United States AI NIAID NIH HHS; R01 AI073098 United States AI NIAID NIH HHS; R25 GM056901 United States GM NIGMS NIH HHS; Canada CAPMC CIHR; AI094715 United States AI NIAID NIH HHS; AI074389 United States AI NIAID NIH HHS

0 (Aptamers, Nucleotide)
0 (Nucleotides)
0 (Organophosphonates)
0 (Reverse Transcriptase Inhibitors)
4B9XT59T7S (Zidovudine)
9007-49-2 (DNA)
99YXE507IL (Tenofovir)
EC 2.7.7.- (reverse transcriptase, Human immunodeficiency virus 1)
EC 2.7.7.49 (HIV Reverse Transcriptase)
EC 2.7.7.49 (RNA-Directed DNA Polymerase)
EC 3.2.1.23 (beta-Galactosidase)
JAC85A2161 (Adenine)

Date Created: 20110913 Date Completed: 20120227 Latest Revision: 20211020

20231215

PMC3245923

10.1093/nar/gkr694

21908397