The evolution of HIV-1 reverse transcriptase in route to acquisition of Q151M multi-drug resistance is complex and involves mutations in multiple domains

Jean Mbisa*, Ravi K. Gupta, Desire Kabamba, Veronica Mulenga, Moxmalama Kalumbi, Chifumbe Chintu, Chris M. Parry, Diana M. Gibb, Sarah A. Walker, Patricia Cane, Deenan Pillay

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Background: The Q151M multi-drug resistance (MDR) pathway in HIV-1 reverse transcriptase (RT) confers reduced susceptibility to all nucleoside reverse transcriptase inhibitors (NRTIs) excluding tenofovir (TDF). This pathway emerges after long term failure of therapy, and is increasingly observed in the resource poor world, where antiretroviral therapy is rarely accompanied by intensive virological monitoring. In this study we examined the genotypic, phenotypic and fitness correlates associated with the development of Q151M MDR in the absence of viral load monitoring.Results: Single-genome sequencing (SGS) of full-length RT was carried out on sequential samples from an HIV-infected individual enrolled in ART rollout. The emergence of Q151M MDR occurred in the order A62V, V75I, and finally Q151M on the same genome at 4, 17 and 37 months after initiation of therapy, respectively. This was accompanied by a parallel cumulative acquisition of mutations at 20 other codon positions; seven of which were located in the connection subdomain. We established that fourteen of these mutations are also observed in Q151M-containing sequences submitted to the Stanford University HIV database. Phenotypic drug susceptibility testing demonstrated that the Q151M-containing RT had reduced susceptibility to all NRTIs except for TDF. RT domain-swapping of patient and wild-type RTs showed that patient-derived connection subdomains were not associated with reduced NRTI susceptibility. However, the virus expressing patient-derived Q151M RT at 37 months demonstrated ~44% replicative capacity of that at 4 months. This was further reduced to ~22% when the Q151M-containing DNA pol domain was expressed with wild-type C-terminal domain, but was then fully compensated by coexpression of the coevolved connection subdomain.Conclusions: We demonstrate a complex interplay between drug susceptibility and replicative fitness in the acquisition Q151M MDR with serious implications for second-line regimen options. The acquisition of the Q151M pathway occurred sequentially over a long period of failing NRTI therapy, and was associated with mutations in multiple RT domains.

Original languageEnglish
Article number31
JournalRetrovirology
Volume8
DOIs
Publication statusPublished - 11 May 2011

Bibliographical note

Funding Information:
We especially thank Sarah Palmer for technical advice in establishing the single-genome sequencing assay; Vinay Pathak, Stéphane Hué, and Andrew Buckton for helpful discussions; the patients, staff and project management of the CHAP2 cohort study in Lusaka, Zambia. We thank Nigel Temperton University of Kent for pCSFLW; Didier Trono EPFL Switzerland for pCMV-Δ8.91 and pMDG; and Thumbi Ndung’u, Boris Renjifo and Max Essex for p8MJ4. We also thank Soo-Yoon Rhee, Stanford University HIV database for help with database sequence analysis and Ross Harris, Health Protection Agency for help with statistical analysis. This report is work financially supported by the National Institute for Health Research in Health Protection at the Health Protection Agency. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. DP is part funded by the NIHR UCLH/UCL Comprehensive Biomedical Research Centre and we acknowledge part funding from the UK Medical Research Council, the Wellcome Trust and the European Community’s Seventh Framework Programme (FP7/2007-2013) under the project “Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN)” - grant agreement n° 223131.

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