Header

UZH-Logo

Maintenance Infos

Systematic screening of viral and human genetic variation identifies antiretroviral resistance and immune escape link


Abstract

Background

Considering the remaining threat of drug-resistantmutations (DRMs) to antiretroviral treatment (ART) efficacy, we investigated how the selective pressure of human leukocyte antigen (HLA)-restricted cytotoxic T lymphocytes drives certain DRMs' emergence and retention.

Methods

We systematically screened DRM:HLA class I allele combinations in 3997 ART-naïve Swiss HIV Cohort Study (SHCS) patients. For each pair, a logistic regression model preliminarily tested for an association with the DRM as the outcome. The three HLA:DRM pairs remaining after multiple testing adjustment were analyzed in three ways: cross-sectional logistic regression models to determine any HLA/infection time interaction, survival analyses to examine if HLA type correlated with developing specific DRMs, and via NetMHCpan to find epitope binding evidence of immune escape.

Results

Only one pair, RT-E138:HLA-B18, exhibited a significant interaction between infection duration and HLA. The survival analyses predicted two pairs with an increased hazard of developing DRMs: RT-E138:HLA-B18 and RT-V179:HLA-B35. RT-E138:HLA-B18 exhibited the greatest significance in both analyses (interaction term odds ratio [OR] 1.169 [95% confidence interval (CI) 1.075-1.273]; p-value<0.001; survival hazard ratio 12.211 [95% CI 3.523-42.318]; p-value<0.001). The same two pairs were also predicted by netMHCpan to have epitopic binding.

Conclusions

We identified DRM:HLA pairs where HLA presence is associated with the presence or emergence of the DRM, indicating that the selective pressure for these mutations alternates direction depending on the presence of these HLA alleles.

Funding

Funded by the Swiss National Science Foundation within the framework of the SHCS, and the University of Zurich, University Research Priority Program: Evolution in Action: From Genomes Ecosystems, in Switzerland.

Abstract

Background

Considering the remaining threat of drug-resistantmutations (DRMs) to antiretroviral treatment (ART) efficacy, we investigated how the selective pressure of human leukocyte antigen (HLA)-restricted cytotoxic T lymphocytes drives certain DRMs' emergence and retention.

Methods

We systematically screened DRM:HLA class I allele combinations in 3997 ART-naïve Swiss HIV Cohort Study (SHCS) patients. For each pair, a logistic regression model preliminarily tested for an association with the DRM as the outcome. The three HLA:DRM pairs remaining after multiple testing adjustment were analyzed in three ways: cross-sectional logistic regression models to determine any HLA/infection time interaction, survival analyses to examine if HLA type correlated with developing specific DRMs, and via NetMHCpan to find epitope binding evidence of immune escape.

Results

Only one pair, RT-E138:HLA-B18, exhibited a significant interaction between infection duration and HLA. The survival analyses predicted two pairs with an increased hazard of developing DRMs: RT-E138:HLA-B18 and RT-V179:HLA-B35. RT-E138:HLA-B18 exhibited the greatest significance in both analyses (interaction term odds ratio [OR] 1.169 [95% confidence interval (CI) 1.075-1.273]; p-value<0.001; survival hazard ratio 12.211 [95% CI 3.523-42.318]; p-value<0.001). The same two pairs were also predicted by netMHCpan to have epitopic binding.

Conclusions

We identified DRM:HLA pairs where HLA presence is associated with the presence or emergence of the DRM, indicating that the selective pressure for these mutations alternates direction depending on the presence of these HLA alleles.

Funding

Funded by the Swiss National Science Foundation within the framework of the SHCS, and the University of Zurich, University Research Priority Program: Evolution in Action: From Genomes Ecosystems, in Switzerland.

Statistics

Citations

Altmetrics

Downloads

0 downloads since deposited on 14 Oct 2021
0 downloads since 12 months

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Infectious Diseases
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > General Neuroscience
Life Sciences > General Biochemistry, Genetics and Molecular Biology
Life Sciences > General Immunology and Microbiology
Language:English
Date:1 June 2021
Deposited On:14 Oct 2021 07:18
Last Modified:15 Oct 2021 20:00
Publisher:eLife Sciences Publications Ltd.
ISSN:2050-084X
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.7554/eLife.67388
PubMed ID:34061023

Download

Gold Open Access

Download PDF  'Systematic screening of viral and human genetic variation identifies antiretroviral resistance and immune escape link'.
Preview
Content: Published Version
Filetype: PDF
Size: 1MB
View at publisher
Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)