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

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

doi:10.3389/fmicb.2021.812391

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.

Highlights

Combinational antiretroviral therapy has significantly slowed the AIDS pandemic and reduced the incidence of HIV infections (UNAIDS, 2020)
In an ecological analysis of pooled viral genomic data from Cameroon where HIV prevalence stands at ∼3.7% in 2021, we used computational and structural methods to assess the genomic plasticity of HIV-1 pol over time and its implication on treatment
Our study revealed high plasticity in HIV-1 pol on the population level, which appears to be profoundly shaped by regionally applied Combinational antiretroviral therapy (cART) protocols

Summary

Introduction

Combinational antiretroviral therapy (cART) has significantly slowed the AIDS pandemic and reduced the incidence of HIV infections (UNAIDS, 2020). Non-clade B infections make up most HIV-1 infections worldwide, with genetic variation among clades up to 35% (Hemelaar et al, 2020) Occurring polymorphisms, their diversity and plasticity, cART-associated viral adaptations, and the growing proportion of DRMs are areas of intense clinical interest and still unfolding. Comprehensive, populationwide studies are required to leverage a deeper understanding of these mutations and NOPs, including effective prevention and treatment strategies We provided such an analysis for Cameroon, a West-Central African country with a population of ∼27 million and ∼3.7% HIV prevalence in 2021, and we considered all functional, non-clonal reverse transcriptase (RT), protease (PR), and integrase (IN) sequences that have been deposited to the LANL database (8,130 out of ∼10,600 submitted sequences in total) (Figure 1)

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Methods

Conclusion