Dataset Information

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

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.

SUBMITTER: Tao K

PROVIDER: S-EPMC10143361 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Tao Kaiming K Rhee Soo-Yon SY Tzou Philip L PL Osman Zachary A ZA Pond Sergei L Kosakovsky SLK Holmes Susan P SP Shafer Robert W RW

Viruses 20230418 4

<h4>Background</h4>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.<h4>Methods</h4>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 in ...[more]

PMID: 37112972

Similar Datasets

Project description:Despite the fidelity of host cell polymerases, the human papillomavirus (HPV) displays a degree of genomic polymorphism resulting in distinct genotypes and intra-type variants. The current HPV vaccines target the most prevalent genotypes associated with cervical cancer (HPV16/18) and genital warts (HPV6/11). Although these vaccines confer some measure of cross-protection, a multivalent HPV vaccine is in the pipeline that aims to broaden vaccine protection against other cervical cancer-associated genotypes including HPV31, HPV33, HPV45, HPV52 and HPV58. Both current and next generation vaccines comprise virus-like particles, based upon the major capsid protein, L1, and vaccine-induced, type-specific protection is likely mediated by neutralizing antibodies targeting L1 surface-exposed domains. The aim of this study was to perform an in silico analysis of existing full length L1 sequences representing vaccine-relevant HPV genotypes in order to address the degree of naturally-occurring, intra-type polymorphisms. In total, 1281 sequences from the Americas, Africa, Asia and Europe were assembled. Intra-type entropy was low and/or limited to non-surface-exposed residues for HPV6, HPV11 and HPV52 suggesting a minimal effect on vaccine antibodies for these genotypes. For HPV16, intra-type entropy was high but the present analysis did not reveal any significant polymorphisms not previously identified. For HPV31, HPV33, HPV58, however, intra-type entropy was high, mostly mapped to surface-exposed domains and in some cases within known neutralizing antibody epitopes. For HPV18 and HPV45 there were too few sequences for a definitive analysis, but HPV45 displayed some degree of surface-exposed residue diversity. In most cases, the reference sequence for each genotype represented a minority variant and the consensus L1 sequences for HPV18, HPV31, HPV45 and HPV58 did not reflect the L1 sequence of the currently available HPV pseudoviruses. These data highlight a number of variant amino acid residues that warrant further investigation for vaccine and natural history studies of HPV.

Project description:BackgroundHIV-1 is highly variable genetically and at protein level, a property it uses to subvert antiviral immunity and treatment. The aim of this study was to assess if HIV subtype differences were associated with variations in glycosylation patterns and co-receptor tropism among HAART patients experiencing different virologic treatment outcomes.MethodsA total of 118 HIV env C2V3 sequence isolates generated previously from 59 Kenyan patients receiving highly active antiretroviral therapy (HAART) were examined for tropism and glycosylation patterns. For analysis of Potential N-linked glycosylation sites (PNGs), amino acid sequences generated by the NCBI's Translate tool were applied to the HIVAlign and the N-glycosite tool within the Los Alamos Database. Viral tropism was assessed using Geno2Pheno (G2P), WebPSSM and Phenoseq platforms as well as using Raymond's and Esbjörnsson's rules. Chi square test was used to determine independent variables association and ANOVA applied on scale variables.ResultsAt respective False Positive Rate (FPR) cut-offs of 5% (p = 0.045), 10% (p = 0.016) and 20% (p = 0.005) for CXCR4 usage within the Geno2Pheno platform, HIV-1 subtype and viral tropism were significantly associated in a chi square test. Raymond's rule (p = 0.024) and WebPSSM (p = 0.05), but not Phenoseq or Esbjörnsson showed significant associations between subtype and tropism. Relative to other platforms used, Raymond's and Esbjörnsson's rules showed higher proportions of X4 variants, while WebPSSM resulted in lower proportions of X4 variants across subtypes. The mean glycosylation density differed significantly between subtypes at positions, N277 (p = 0.034), N296 (p = 0.036), N302 (p = 0.034) and N366 (p = 0.004), with HIV-1D most heavily glycosylated of the subtypes. R5 isolates had fewer PNGs than X4 isolates, but these differences were not significant except at position N262 (p = 0.040). Cell-associated isolates from virologic treatment success subjects were more glycosylated than cell-free isolates from virologic treatment failures both for the NXT (p = 0.016), and for all the patterns (p = 0.011).ConclusionThese data reveal significant associations of HIV-1 subtype diversity, viral co-receptor tropism, viral suppression and envelope glycosylation. These associations have important implications for designing therapy and vaccines against HIV. Heavy glycosylation and preference for CXCR4 usage of HIV-1D may explain rapid disease progression in patients infected with these strains.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets