Impact of Drug Resistance-associated Amino Acid Changes in HIV-1 Subtype C on Susceptibility to Newer Nonnucleoside Reverse Transcriptase Inhibitors

Overview

Journal Antimicrob Agents Chemother

Publisher American Society for Microbiology

Specialty Pharmacology

Date 2014 Nov 26

PMID 25421485

Citations 34

Authors

Adriaan E Basson

Soo-Yon Rhee

Chris M Parry

Ziad El-Khatib

Salome Charalambous

Tulio de Oliveira

Deenan Pillay

Christopher Hoffmann

David Katzenstein

Robert W Shafer

Lynn Morris

Affiliations

Soon will be listed here.

Abstract

The objective of this study was to assess the phenotypic susceptibility of HIV-1 subtype C isolates, with nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated amino acid changes, to newer NNRTIs. A panel of 52 site-directed mutants and 38 clinically derived HIV-1 subtype C clones was created, and the isolates were assessed for phenotypic susceptibility to etravirine (ETR), rilpivirine (RPV), efavirenz (EFV), and nevirapine (NVP) in an in vitro single-cycle phenotypic assay. The amino acid substitutions E138Q/R, Y181I/V, and M230L conferred high-level resistance to ETR, while K101P and Y181I/V conferred high-level resistance to RPV. Y181C, a major NNRTI resistance-associated amino acid substitution, caused decreased susceptibility to ETR and, to a lesser extent, RPV when combined with other mutations. These included N348I and T369I, amino acid changes in the connection domain that are not generally assessed during resistance testing. However, the prevalence of these genotypes among subtype C sequences was, in most cases, <1%. The more common EFV/NVP resistance-associated substitutions, such as K103N, V106M, and G190A, had no major impact on ETR or RPV susceptibility. The low-level resistance to RPV and ETR conferred by E138K was not significantly enhanced in the presence of M184V/I, unlike for EFV and NVP. Among patient samples, 97% were resistant to EFV and/or NVP, while only 24% and 16% were resistant to ETR and RPV, respectively. Overall, only a few, relatively rare NNRTI resistance-associated amino acid substitutions caused resistance to ETR and/or RPV in an HIV-1 subtype C background, suggesting that these newer NNRTIs would be effective in NVP/EFV-experienced HIV-1 subtype C-infected patients.

Citing Articles

Identification of a novel small-molecule inhibitor of the HIV-1 reverse transcriptase activity with a non-nucleoside mode of action.

Yu K, Shin Y, Kim D, Kim J, Kang J, Singh P Virol J. 2025; 22(1):65.

PMID: 40055750 PMC: 11887385. DOI: 10.1186/s12985-025-02680-3.

Virulence and Replicative Fitness of HIV-1 Transmitted/Founder (T/F) Viruses Harbouring Drug Resistance-Associated Mutation.

Sonawane A, Selvam D, Yue L, Nesakumar M, Vivekanandan S, Ashokkumar M Viruses. 2025; 16(12.

PMID: 39772167 PMC: 11680346. DOI: 10.3390/v16121854.

K103N, V106M and Y188L Significantly Reduce HIV-1 Subtype C Phenotypic Susceptibility to Doravirine.

Reddy N, Papathanasopoulos M, Steegen K, Basson A Viruses. 2024; 16(9).

PMID: 39339969 PMC: 11437401. DOI: 10.3390/v16091493.

Decoupling HIV-1 antiretroviral drug inhibition from plasma antibody activity to evaluate broadly neutralizing antibody therapeutics and vaccines.

Schwarzmuller M, Lozano C, Schanz M, Abela I, Grosse-Holz S, Epp S Cell Rep Med. 2024; 5(9):101702.

PMID: 39216479 PMC: 11524982. DOI: 10.1016/j.xcrm.2024.101702.

Chemical inhibition of DPP9 sensitizes the CARD8 inflammasome in HIV-1-infected cells.

Clark K, Kim J, Wang Q, Gao H, Presti R, Shan L Nat Chem Biol. 2022; 19(4):431-439.

PMID: 36357533 PMC: 10065922. DOI: 10.1038/s41589-022-01182-5.

References

Santos A, Soares M . HIV Genetic Diversity and Drug Resistance. Viruses. 2011; 2(2):503-531. PMC: 3185604. DOI: 10.3390/v2020503. View

Katlama C, Clotet B, Mills A, Trottier B, Molina J, Grinsztejn B . Efficacy and safety of etravirine at week 96 in treatment-experienced HIV type-1-infected patients in the DUET-1 and DUET-2 trials. Antivir Ther. 2010; 15(7):1045-52. DOI: 10.3851/IMP1662. View

Johnson V, Calvez V, Gunthard H, Paredes R, Pillay D, Shafer R . Update of the drug resistance mutations in HIV-1: March 2013. Top Antivir Med. 2013; 21(1):6-14. PMC: 6148891. View

Xu H, Oliveira M, Quashie P, McCallum M, Han Y, Quan Y . Subunit-selective mutational analysis and tissue culture evaluations of the interactions of the E138K and M184I mutations in HIV-1 reverse transcriptase. J Virol. 2012; 86(16):8422-31. PMC: 3421741. DOI: 10.1128/JVI.00271-12. View

Vingerhoets J, Tambuyzer L, Azijn H, Hoogstoel A, Nijs S, Peeters M . Resistance profile of etravirine: combined analysis of baseline genotypic and phenotypic data from the randomized, controlled Phase III clinical studies. AIDS. 2010; 24(4):503-14. DOI: 10.1097/QAD.0b013e32833677ac. View

Ruxrungtham K, Pedro R, Latiff G, Conradie F, Domingo P, Lupo S . Impact of reverse transcriptase resistance on the efficacy of TMC125 (etravirine) with two nucleoside reverse transcriptase inhibitors in protease inhibitor-naïve, nonnucleoside reverse transcriptase inhibitor-experienced patients: study TMC125-C227. HIV Med. 2008; 9(10):883-96. DOI: 10.1111/j.1468-1293.2008.00644.x. View

Hu Z, Kuritzkes D . Interaction of reverse transcriptase (RT) mutations conferring resistance to lamivudine and etravirine: effects on fitness and RT activity of human immunodeficiency virus type 1. J Virol. 2011; 85(21):11309-14. PMC: 3194991. DOI: 10.1128/JVI.05578-11. View

Armstrong K, Lee T, Essex M . Replicative fitness costs of nonnucleoside reverse transcriptase inhibitor drug resistance mutations on HIV subtype C. Antimicrob Agents Chemother. 2011; 55(5):2146-53. PMC: 3088272. DOI: 10.1128/AAC.01505-10. View

Melikian G, Rhee S, Varghese V, Porter D, White K, Taylor J . Non-nucleoside reverse transcriptase inhibitor (NNRTI) cross-resistance: implications for preclinical evaluation of novel NNRTIs and clinical genotypic resistance testing. J Antimicrob Chemother. 2013; 69(1):12-20. PMC: 3861329. DOI: 10.1093/jac/dkt316. View

10.

Orrell C, Walensky R, Losina E, Pitt J, Freedberg K, Wood R . HIV type-1 clade C resistance genotypes in treatment-naive patients and after first virological failure in a large community antiretroviral therapy programme. Antivir Ther. 2009; 14(4):523-31. PMC: 3211093. View

11.

Cozzi-Lepri A, Paredes , Phillips A, Clotet B, Kjaer J, von Wyl V . The rate of accumulation of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance in patients kept on a virologically failing regimen containing an NNRTI*. HIV Med. 2011; 13(1):62-72. DOI: 10.1111/j.1468-1293.2011.00943.x. View

12.

Cohen C, Andrade-Villanueva J, Clotet B, Fourie J, Johnson M, Ruxrungtham K . Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial. Lancet. 2011; 378(9787):229-37. DOI: 10.1016/S0140-6736(11)60983-5. View

13.

Geretti A, Harrison L, Green H, Sabin C, Hill T, Fearnhill E . Effect of HIV-1 subtype on virologic and immunologic response to starting highly active antiretroviral therapy. Clin Infect Dis. 2009; 48(9):1296-305. DOI: 10.1086/598502. View

14.

Invernizzi C, Coutsinos D, Oliveira M, Moisi D, Brenner B, Wainberg M . Signature nucleotide polymorphisms at positions 64 and 65 in reverse transcriptase favor the selection of the K65R resistance mutation in HIV-1 subtype C. J Infect Dis. 2009; 200(8):1202-6. DOI: 10.1086/605894. View

15.

Das K, Clark Jr A, Lewi P, Heeres J, de Jonge M, Koymans L . Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1.... J Med Chem. 2004; 47(10):2550-60. DOI: 10.1021/jm030558s. View

16.

Marconi V, Sunpath H, Lu Z, Gordon M, Koranteng-Apeagyei K, Hampton J . Prevalence of HIV-1 drug resistance after failure of a first highly active antiretroviral therapy regimen in KwaZulu Natal, South Africa. Clin Infect Dis. 2008; 46(10):1589-97. PMC: 2692213. DOI: 10.1086/587109. View

17.

Buckheit Jr R . Understanding HIV resistance, fitness, replication capacity and compensation: targeting viral fitness as a therapeutic strategy. Expert Opin Investig Drugs. 2004; 13(8):933-58. DOI: 10.1517/13543784.13.8.933. View

18.

Zhang J, Rhee S, Taylor J, Shafer R . Comparison of the precision and sensitivity of the Antivirogram and PhenoSense HIV drug susceptibility assays. J Acquir Immune Defic Syndr. 2005; 38(4):439-44. PMC: 2547471. DOI: 10.1097/01.qai.0000147526.64863.53. View

19.

Wainberg M, Brenner B . The Impact of HIV Genetic Polymorphisms and Subtype Differences on the Occurrence of Resistance to Antiretroviral Drugs. Mol Biol Int. 2012; 2012:256982. PMC: 3390109. DOI: 10.1155/2012/256982. View

20.

Rimsky L, Van Eygen V, Hoogstoel A, Stevens M, Boven K, Picchio G . 96-Week resistance analyses of rilpivirine in treatment-naive, HIV-1-infected adults from the ECHO and THRIVE Phase III trials. Antivir Ther. 2013; 18(8):967-77. DOI: 10.3851/IMP2636. View