Antiretroviral Imprints and Genomic Plasticity of HIV-1 pol in Non-clade B: Implications for Treatment

Jude S Bimela; Aubin J Nanfack; Pengpeng Yang; Shaoxing Dai; Xiang-Peng Kong; Judith N Torimiro; Ralf Duerr

doi:10.3389/fmicb.2021.812391

Antiretroviral Imprints and Genomic Plasticity of HIV-1 pol in Non-clade B: Implications for Treatment

Front Microbiol. 2022 Feb 9:12:812391. doi: 10.3389/fmicb.2021.812391. eCollection 2021.

Authors

Jude S Bimela^{1

2

3}, Aubin J Nanfack^{4

5}, Pengpeng Yang⁶, Shaoxing Dai⁶, Xiang-Peng Kong⁷, Judith N Torimiro^{5

8}, Ralf Duerr^{1

9}

Affiliations

¹ Department of Pathology, New York University School of Medicine, New York, NY, United States.
² Department of Biochemistry, University of Yaoundé 1, Yaoundé, Cameroon.
³ Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, United States.
⁴ Medical Diagnostic Center, Yaoundé, Cameroon.
⁵ Chantal Biya International Reference Centre for Research on HIV/AIDS Prevention and Management (CIRCB), Yaoundé, Cameroon.
⁶ Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China.
⁷ Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, United States.
⁸ Department of Biochemistry, Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, Yaoundé, Cameroon.
⁹ Department of Microbiology, New York University School of Medicine, New York, NY, United States.

Abstract

Combinational antiretroviral therapy (cART) is the most effective tool to prevent and control HIV-1 infection without an effective vaccine. However, HIV-1 drug resistance mutations (DRMs) and naturally occurring polymorphisms (NOPs) can abrogate cART efficacy. Here, we aimed to characterize the HIV-1 pol mutation landscape in Cameroon, where highly diverse HIV clades circulate, and identify novel treatment-associated mutations that can potentially affect cART efficacy. More than 8,000 functional Cameroonian HIV-1 pol sequences from 1987 to 2020 were studied for DRMs and NOPs. Site-specific amino acid frequencies and quaternary structural features were determined and compared between periods before (≤2003) and after (2004-2020) regional implementation of cART. cART usage in Cameroon induced deep mutation imprints in reverse transcriptase (RT) and to a lower extent in protease (PR) and integrase (IN), according to their relative usage. In the predominant circulating recombinant form (CRF) 02_AG (CRF02_AG), 27 canonical DRMs and 29 NOPs significantly increased or decreased in RT during cART scale-up, whereas in IN, no DRM and only seven NOPs significantly changed. The profound genomic imprints and higher prevalence of DRMs in RT compared to PR and IN mirror the dominant use of reverse transcriptase inhibitors (RTIs) in sub-Saharan Africa and the predominantly integrase strand transfer inhibitor (InSTI)-naïve study population. Our results support the potential of InSTIs for antiretroviral treatment in Cameroon; however, close surveillance of IN mutations will be required to identify emerging resistance patterns, as observed in RT and PR. Population-wide genomic analyses help reveal the presence of selective pressures and viral adaptation processes to guide strategies to bypass resistance and reinstate effective treatment.

Keywords: CRF02_AG; HIV-1 polymerase (pol); antiretroviral imprints; genomic plasticity; naturally occurring polymorphisms (NOPs); non-clade B drug resistance mutations (DRMs); reverse transcriptase inhibitors (RTI) versus integrase strand transfer inhibitors (INSTI); treatment intensification in Cameroon.