A Novel Point Mutation at Position 156 of Reverse Transcriptase from Feline Immunodeficiency Virus Confers Resistance to the Combination of (-)-beta-2',3'-dideoxy-3'-thiacytidine and 3'-azido-3'-deoxythymidine

Overview

Journal J Virol

Publisher American Society for Microbiology

Date 1998 Mar 14

PMID 9499094

Citations 11

Authors

R A Smith

K M Remington

B D Preston

R F Schinazi

T W North

Affiliations

Soon will be listed here.

Abstract

Mutants of feline immunodeficiency virus (FIV) resistant to (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC) were selected by culturing virus in the presence of increasing stepwise concentrations of 3TC. Two plaque-purified variants were isolated from the original mutant population, and both of these mutants were resistant to 3TC. Surprisingly, these mutants were also phenotypically resistant to 3'-azido-3'-deoxythymidine (AZT) and to the combination of 3TC and AZT. Purified reverse transcriptase (RT) from one of these plaque-purified mutants was resistant to the 5'-triphosphates of 3TC and AZT. DNA sequence analysis of the RT-encoding region of the pol gene amplified from the plaque-purified mutants revealed a Pro-to-Ser mutation at position 156 of RT. A site-directed mutant of FIV engineered to contain this Pro-156-Ser mutation was resistant to 3TC, AZT, and the combination of 3TC and AZT, confirming the role of the Pro-156-Ser mutation in the resistance of FIV to these two nucleoside analogs. This represents the first report of a lentiviral mutant resistant to the combination of AZT and 3TC due to a single, unique point mutation.

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References

Ding J, Nanni R, Clark Jr A, Lu X, Tantillo C, Williams R . Crystal structure of human immunodeficiency virus type 1 reverse transcriptase complexed with double-stranded DNA at 3.0 A resolution shows bent DNA. Proc Natl Acad Sci U S A. 1993; 90(13):6320-4. PMC: 46920. DOI: 10.1073/pnas.90.13.6320. View

Gao Q, Gu Z, Parniak M, Li X, Wainberg M . In vitro selection of variants of human immunodeficiency virus type 1 resistant to 3'-azido-3'-deoxythymidine and 2',3'-dideoxyinosine. J Virol. 1992; 66(1):12-9. PMC: 238254. DOI: 10.1128/JVI.66.1.12-19.1992. View

Gao Q, Gu Z, Parniak M, Cameron J, Cammack N, Boucher C . The same mutation that encodes low-level human immunodeficiency virus type 1 resistance to 2',3'-dideoxyinosine and 2',3'-dideoxycytidine confers high-level resistance to the (-) enantiomer of 2',3'-dideoxy-3'-thiacytidine. Antimicrob Agents Chemother. 1993; 37(6):1390-2. PMC: 187976. DOI: 10.1128/AAC.37.6.1390. View

Otto M, Garber S, Winslow D, Reid C, ALDRICH P, Jadhav P . In vitro isolation and identification of human immunodeficiency virus (HIV) variants with reduced sensitivity to C-2 symmetrical inhibitors of HIV type 1 protease. Proc Natl Acad Sci U S A. 1993; 90(16):7543-7. PMC: 47178. DOI: 10.1073/pnas.90.16.7543. View

Mathez D, Schinazi R, Liotta D, Leibowitch J . Infectious amplification of wild-type human immunodeficiency virus from patients' lymphocytes and modulation by reverse transcriptase inhibitors in vitro. Antimicrob Agents Chemother. 1993; 37(10):2206-11. PMC: 192251. DOI: 10.1128/AAC.37.10.2206. View

Boucher C, Cammack N, Schipper P, Schuurman R, Rouse P, Wainberg M . High-level resistance to (-) enantiomeric 2'-deoxy-3'-thiacytidine in vitro is due to one amino acid substitution in the catalytic site of human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother. 1993; 37(10):2231-4. PMC: 192256. DOI: 10.1128/AAC.37.10.2231. View

Remington K, Zhu Y, Phillips T, North T . Rapid phenotypic reversion of zidovudine-resistant feline immunodeficiency virus without loss of drug-resistant reverse transcriptase. J Virol. 1994; 68(2):632-7. PMC: 236496. DOI: 10.1128/JVI.68.2.632-637.1994. View

Fitzgibbon J, Howell R, Haberzettl C, Sperber S, Gocke D, DUBIN D . Human immunodeficiency virus type 1 pol gene mutations which cause decreased susceptibility to 2',3'-dideoxycytidine. Antimicrob Agents Chemother. 1992; 36(1):153-7. PMC: 189244. DOI: 10.1128/AAC.36.1.153. View

Kohlstaedt L, Wang J, Friedman J, Rice P, Steitz T . Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science. 1992; 256(5065):1783-90. DOI: 10.1126/science.1377403. View

10.

Cronn R, Remington K, Preston B, North T . Inhibition of reverse transcriptase from feline immunodeficiency virus by analogs of 2'-deoxyadenosine-5'-triphosphate. Biochem Pharmacol. 1992; 44(7):1375-81. DOI: 10.1016/0006-2952(92)90539-u. View

11.

Gao Q, Gu Z, Hiscott J, Dionne G, Wainberg M . Generation of drug-resistant variants of human immunodeficiency virus type 1 by in vitro passage in increasing concentrations of 2',3'-dideoxycytidine and 2',3'-dideoxy-3'-thiacytidine. Antimicrob Agents Chemother. 1993; 37(1):130-3. PMC: 187620. DOI: 10.1128/AAC.37.1.130. View

12.

Schinazi R, Lloyd Jr R, Nguyen M, Cannon D, McMillan A, Ilksoy N . Characterization of human immunodeficiency viruses resistant to oxathiolane-cytosine nucleosides. Antimicrob Agents Chemother. 1993; 37(4):875-81. PMC: 187791. DOI: 10.1128/AAC.37.4.875. View

13.

Podell M, Oglesbee M, Mathes L, Krakowka S, Olmstead R, Lafrado L . AIDS-associated encephalopathy with experimental feline immunodeficiency virus infection. J Acquir Immune Defic Syndr (1988). 1993; 6(7):758-71. View

14.

Tisdale M, Kemp S, Parry N, Larder B . Rapid in vitro selection of human immunodeficiency virus type 1 resistant to 3'-thiacytidine inhibitors due to a mutation in the YMDD region of reverse transcriptase. Proc Natl Acad Sci U S A. 1993; 90(12):5653-6. PMC: 46779. DOI: 10.1073/pnas.90.12.5653. View

15.

Richman D, Havlir D, Corbeil J, Looney D, Ignacio C, Spector S . Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. J Virol. 1994; 68(3):1660-6. PMC: 236624. DOI: 10.1128/JVI.68.3.1660-1666.1994. View

16.

Shafer R, Kozal M, Winters M, Iversen A, Katzenstein D, Ragni M . Combination therapy with zidovudine and didanosine selects for drug-resistant human immunodeficiency virus type 1 strains with unique patterns of pol gene mutations. J Infect Dis. 1994; 169(4):722-9. DOI: 10.1093/infdis/169.4.722. View

17.

Phillips T, Prospero-Garcia O, Puaoi D, Lerner D, Fox H, Olmsted R . Neurological abnormalities associated with feline immunodeficiency virus infection. J Gen Virol. 1994; 75 ( Pt 5):979-87. DOI: 10.1099/0022-1317-75-5-979. View

18.

Gu Z, Gao Q, Fang H, Salomon H, Parniak M, Goldberg E . Identification of a mutation at codon 65 in the IKKK motif of reverse transcriptase that encodes human immunodeficiency virus resistance to 2',3'-dideoxycytidine and 2',3'-dideoxy-3'-thiacytidine. Antimicrob Agents Chemother. 1994; 38(2):275-81. PMC: 284440. DOI: 10.1128/AAC.38.2.275. View

19.

North T, Hansen G, Zhu Y, Griffin J, Shih C . Expression of reverse transcriptase from feline immunodeficiency virus in Escherichia coli. Antimicrob Agents Chemother. 1994; 38(2):388-91. PMC: 284465. DOI: 10.1128/AAC.38.2.388. View

20.

KAPLAN A, Michael S, Wehbie R, Knigge M, Paul D, Everitt L . Selection of multiple human immunodeficiency virus type 1 variants that encode viral proteases with decreased sensitivity to an inhibitor of the viral protease. Proc Natl Acad Sci U S A. 1994; 91(12):5597-601. PMC: 44043. DOI: 10.1073/pnas.91.12.5597. View