Persistence Versus Reversion of 3TC Resistance in HIV-1 Determine the Rate of Emergence of NVP Resistance

Overview

Journal Viruses

Publisher MDPI

Specialty Microbiology

Date 2012 Sep 27

PMID 23012621

Citations 2

Authors

Barbara A Rath

Richard A Olshen

Jerry Halpern

Thomas C Merigan

Affiliations

Soon will be listed here.

Abstract

When HIV-1 is exposed to lamivudine (3TC) at inhibitory concentrations, resistant variants carrying the reverse transcriptase (RT) substitution M184V emerge rapidly. This substitution confers high-level 3TC resistance and increased RT fidelity. We established a novel in vitro system to study the effect of starting nevirapine (NVP) in 3TC-resistant/NNRTI-naïve clinical isolates, and the impact of maintaining versus dropping 3TC pressure in this setting. Because M184V mutant HIV-1 seems hypersusceptible to adefovir (ADV), we also tested the effect of ADV pressure on the same isolates. We draw four conclusions from our experiments simulating combination therapy in vitro. (1) The presence of low-dose (1 μM) 3TC prevented reversal to wild-type from an M184V mutant background. (2) Adding low-dose 3TC in the presence of NVP delayed the selection of NVP-associated mutations. (3) The presence of ADV, in addition to NVP, led to more rapid reversal to wild-type at position 184 than NVP alone. (4) ADV plus NVP selected for greater numbers of mutations than NVP alone. Inference about the "selection of mutation" is based on two statistical models, one at the viral level, more telling, and the other at the level of predominance of mutation within a population. Multidrug pressure experiments lend understanding to mechanisms of HIV resistance as they bear upon new treatment strategies.

Citing Articles

Advancing challenges in Paediatric Virology: An interview with Professor Barbara A. Rath, Co-founder and Chair of the Vienna Vaccine Safety Initiative.

Mammas I, Spandidos D Exp Ther Med. 2019; 18(4):3231-3237.

PMID: 31588214 PMC: 6766581. DOI: 10.3892/etm.2019.7948.

In vitro HIV-1 evolution in response to triple reverse transcriptase inhibitors & in silico phenotypic analysis.

Rath B, Yousef K, Katzenstein D, Shafer R, Schutte C, von Kleist M PLoS One. 2013; 8(4):e61102.

PMID: 23613794 PMC: 3629221. DOI: 10.1371/journal.pone.0061102.

References

Sierra-Aragon S, Walter H . Targets for inhibition of HIV replication: entry, enzyme action, release and maturation. Intervirology. 2012; 55(2):84-97. DOI: 10.1159/000331995. View

Diallo K, Brenner B, Oliveira M, Moisi D, Detorio M, Gotte M . The M184V substitution in human immunodeficiency virus type 1 reverse transcriptase delays the development of resistance to amprenavir and efavirenz in subtype B and C clinical isolates. Antimicrob Agents Chemother. 2003; 47(7):2376-9. PMC: 161854. DOI: 10.1128/AAC.47.7.2376-2379.2003. View

Diallo K, Oliveira M, Moisi D, Brenner B, Wainberg M, Gotte M . Pressure of zidovudine accelerates the reversion of lamivudine resistance-conferring M184V mutation in the reverse transcriptase of human immunodeficiency virus type 1. Antimicrob Agents Chemother. 2002; 46(7):2254-6. PMC: 127311. DOI: 10.1128/AAC.46.7.2254-2256.2002. View

Sarafianos S, Das K, Clark Jr A, Ding J, Boyer P, Hughes S . Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with beta-branched amino acids. Proc Natl Acad Sci U S A. 1999; 96(18):10027-32. PMC: 17836. DOI: 10.1073/pnas.96.18.10027. View

Shafer R, Hertogs K, Zolopa A, Warford A, Bloor S, Betts B . High degree of interlaboratory reproducibility of human immunodeficiency virus type 1 protease and reverse transcriptase sequencing of plasma samples from heavily treated patients. J Clin Microbiol. 2001; 39(4):1522-9. PMC: 87964. DOI: 10.1128/JCM.39.4.1522-1529.2001. View

Schapiro J, Winters M, Stewart F, Efron B, Norris J, Kozal M . The effect of high-dose saquinavir on viral load and CD4+ T-cell counts in HIV-infected patients. Ann Intern Med. 1996; 124(12):1039-50. DOI: 10.7326/0003-4819-124-12-199606150-00003. View

Petrella M, Wainberg M . Might the M184V substitution in HIV-1 RT confer clinical benefit?. AIDS Rev. 2003; 4(4):224-32. View

Miller M, Anton K, Mulato A, Lamy P, Cherrington J . Human immunodeficiency virus type 1 expressing the lamivudine-associated M184V mutation in reverse transcriptase shows increased susceptibility to adefovir and decreased replication capability in vitro. J Infect Dis. 1998; 179(1):92-100. DOI: 10.1086/314560. View

Camacho R, Teofilo E . Antiretroviral therapy in treatment-naïve patients with HIV infection. Curr Opin HIV AIDS. 2011; 6 Suppl 1:S3-11. DOI: 10.1097/01.COH.0000410239.88517.00. View

10.

Baxter J, Mayers D, Wentworth D, Neaton J, HOOVER M, Winters M . A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy. CPCRA 046 Study Team for the Terry Beirn Community Programs for Clinical Research on AIDS. AIDS. 2000; 14(9):F83-93. DOI: 10.1097/00002030-200006160-00001. View

11.

Turner D, Brenner B, Routy J, Petrella M, Wainberg M . Rationale for maintenance of the M184v resistance mutation in human immunodeficiency virus type 1 reverse transcriptase in treatment experienced patients. New Microbiol. 2005; 27(2 Suppl 1):31-9. View

12.

Mansky L, Cunningham K . Virus mutators and antimutators: roles in evolution, pathogenesis and emergence. Trends Genet. 2000; 16(11):512-7. DOI: 10.1016/s0168-9525(00)02125-9. View

13.

Opravil M, Klimkait T, Louvel S, Wolf E, Battegay M, Fux C . Prior therapy influences the efficacy of lamivudine monotherapy in patients with lamivudine-resistant HIV-1 infection. J Acquir Immune Defic Syndr. 2009; 54(1):51-8. DOI: 10.1097/QAI.0b013e3181bef889. View

14.

Stumpp S, Heyn B, Brakmann S . Activity-based selection of HIV-1 reverse transcriptase variants with decreased polymerization fidelity. Biol Chem. 2010; 391(6):665-74. DOI: 10.1515/BC.2010.067. View

15.

Kekitiinwa A, Asiimwe A, Kasirye P, Korutaro V, Kitaka S, Maganda A . Prospective long-term outcomes of a cohort of Ugandan children with laboratory monitoring during antiretroviral therapy. Pediatr Infect Dis J. 2012; 31(8):e117-25. DOI: 10.1097/INF.0b013e31825cb9d6. View

16.

Winters M, Holodniy M, Katzenstein D, Merigan T . Quantitative RNA and DNA gene amplification can rapidly monitor HIV infection and antiviral activity in cell cultures. PCR Methods Appl. 1992; 1(4):257-62. DOI: 10.1101/gr.1.4.257. View

17.

Rouleau D, Fortin C, Trottier B, Lalonde R, Lapointe N, Cote P . Antiretroviral therapy for adults infected with HIV: Guidelines for health care professionals from the Quebec HIV care committee. Can J Infect Dis Med Microbiol. 2012; 22(2):52-60. PMC: 3142594. DOI: 10.1155/2011/169045. View

18.

Campbell T, Shulman N, Johnson S, Zolopa A, Young R, Bushman L . Antiviral activity of lamivudine in salvage therapy for multidrug-resistant HIV-1 infection. Clin Infect Dis. 2005; 41(2):236-42. DOI: 10.1086/430709. View

19.

Jonckheere H, Witvrouw M, De Clercq E, Anne J . Lamivudine resistance of HIV type 1 does not delay development of resistance to nonnucleoside HIV type 1-specific reverse transcriptase inhibitors as compared with wild-type HIV type 1. AIDS Res Hum Retroviruses. 1998; 14(3):249-53. DOI: 10.1089/aid.1998.14.249. View

20.

Winters M, Coolley K, Girard Y, Levee D, Hamdan H, Shafer R . A 6-basepair insert in the reverse transcriptase gene of human immunodeficiency virus type 1 confers resistance to multiple nucleoside inhibitors. J Clin Invest. 1998; 102(10):1769-75. PMC: 509125. DOI: 10.1172/JCI4948. View