HIV-1 Group M Capsid Amino Acid Variability: Implications for Sequence Quality Control of Genotypic Resistance Testing

Author:

Tao Kaiming1ORCID,Rhee Soo-Yon1ORCID,Tzou Philip L.1ORCID,Osman Zachary A.1,Pond Sergei L. Kosakovsky2ORCID,Holmes Susan P.3,Shafer Robert W.1ORCID

Affiliation:

1. Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, CA 94305, USA

2. Institute for Genomics and Evolutionary Medicine, Temple University, Philadelphia, PA 19122, USA

3. Department of Statistics, Stanford University, Stanford, CA 94305, USA

Abstract

Background: With the approval of the HIV-1 capsid inhibitor, lenacapavir, capsid sequencing will be required for managing lenacapavir-experienced individuals with detectable viremia. Successful sequence interpretation will require examining new capsid sequences in the context of previously published sequence data. Methods: We analyzed published HIV-1 group M capsid sequences from 21,012 capsid-inhibitor naïve individuals to characterize amino acid variability at each position and influence of subtype and cytotoxic T lymphocyte (CTL) selection pressure. We determined the distributions of usual mutations, defined as amino acid differences from the group M consensus, with a prevalence ≥ 0.1%. Co-evolving mutations were identified using a phylogenetically-informed Bayesian graphical model method. Results: 162 (70.1%) positions had no usual mutations (45.9%) or only conservative usual mutations with a positive BLOSUM62 score (24.2%). Variability correlated independently with subtype-specific amino acid occurrence (Spearman rho = 0.83; p < 1 × 10−9) and the number of times positions were reported to contain an HLA-associated polymorphism, an indicator of CTL pressure (rho = 0.43; p = 0.0002). Conclusions: Knowing the distribution of usual capsid mutations is essential for sequence quality control. Comparing capsid sequences from lenacapavir-treated and lenacapavir-naïve individuals will enable the identification of additional mutations potentially associated with lenacapavir therapy.

Funder

NIH/National Institute of Allergy and Infectious Diseases

Publisher

MDPI AG

Subject

Virology,Infectious Diseases

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