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Article: Effects of mutations on replicative fitness and major histocompatibility complex class I binding affinity are among the determinants underlying Cytotoxic-T-Lymphocyte escape of HIV-1 Gag epitopes

TitleEffects of mutations on replicative fitness and major histocompatibility complex class I binding affinity are among the determinants underlying Cytotoxic-T-Lymphocyte escape of HIV-1 Gag epitopes
Authors
KeywordsHIV-I
MHC binding prediction
Intrapatient viral evolution
High-throughput fitness profiling
Gag epitopes
CTL escape
Issue Date2017
Citation
mBio, 2017, v. 8, n. 6, article no. e01050-17 How to Cite?
Abstract© 2017 Du et al. Certain “protective” major histocompatibility complex class I (MHC-I) alleles, such as B*57 and B*27, are associated with long-term control of HIV-1 in vivo mediated by the CD8+ cytotoxic-T-lymphocyte (CTL) response. However, the mechanism of such superior protection is not fully understood. Here we combined high-throughput fitness profiling of mutations in HIV-1 Gag, in silico prediction of MHC-peptide binding affinity, and analysis of intraperson virus evolution to systematically compare differences with respect to CTL escape mutations between epitopes targeted by protective MHC-I alleles and those targeted by nonprotective MHC-I alleles. We observed that the effects of mutations on both viral replication and MHC-I binding affinity are among the determinants of CTL escape. Mutations in Gag epitopes presented by protective MHC-I alleles are associated with significantly higher fitness cost and lower reductions in binding affinity with respect to MHC-I. A linear regression model accounting for the effect of mutations on both viral replicative capacity and MHC-I binding can explain the protective efficacy of MHC-I alleles. Finally, we found a consistent pattern in the evolution of Gag epitopes in long-term nonprogressors versus progressors. Overall, our results suggest that certain protective MHC-I alleles allow superior control of HIV-1 by targeting epitopes where mutations typically incur high fitness costs and small reductions in MHC-I binding affinity. IMPORTANCE Understanding the mechanism of viral control achieved in long-term nonprogressors with protective HLA alleles provides insights for developing functional cure of HIV infection. Through the characterization of CTL escape mutations in infected persons, previous researchers hypothesized that protective alleles target epitopes where escape mutations significantly reduce viral replicative capacity. How-ever, these studies were usually limited to a few mutations observed in vivo. Here we utilized our recently developed high-throughput fitness profiling method to quantitatively measure the fitness of mutations across the entirety of HIV-1 Gag. The data enabled us to integrate the results with in silico prediction of MHC-peptide binding affinity and analysis of intraperson virus evolution to systematically determine the differences in CTL escape mutations between epitopes targeted by protective HLA alleles and those targeted by nonprotective HLA alleles. We observed that the effects of Gag epitope mutations on HIV replicative fitness and MHC-I binding affinity are among the major determinants of CTL escape.
Persistent Identifierhttp://hdl.handle.net/10722/285799
ISSN
2023 SCImago Journal Rankings: 2.028
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorDu, Yushen-
dc.contributor.authorZhang, Tian Hao-
dc.contributor.authorDai, Lei-
dc.contributor.authorZheng, Xiaojuan-
dc.contributor.authorGorin, Aleksandr M.-
dc.contributor.authorOishi, John-
dc.contributor.authorWu, Ting Ting-
dc.contributor.authorYoshizawa, Janice M.-
dc.contributor.authorLi, Xinmin-
dc.contributor.authorYang, Otto O.-
dc.contributor.authorMartinez-Maza, Otoniel-
dc.contributor.authorDetels, Roger-
dc.contributor.authorSun, Ren-
dc.date.accessioned2020-08-18T04:56:40Z-
dc.date.available2020-08-18T04:56:40Z-
dc.date.issued2017-
dc.identifier.citationmBio, 2017, v. 8, n. 6, article no. e01050-17-
dc.identifier.issn2161-2129-
dc.identifier.urihttp://hdl.handle.net/10722/285799-
dc.description.abstract© 2017 Du et al. Certain “protective” major histocompatibility complex class I (MHC-I) alleles, such as B*57 and B*27, are associated with long-term control of HIV-1 in vivo mediated by the CD8+ cytotoxic-T-lymphocyte (CTL) response. However, the mechanism of such superior protection is not fully understood. Here we combined high-throughput fitness profiling of mutations in HIV-1 Gag, in silico prediction of MHC-peptide binding affinity, and analysis of intraperson virus evolution to systematically compare differences with respect to CTL escape mutations between epitopes targeted by protective MHC-I alleles and those targeted by nonprotective MHC-I alleles. We observed that the effects of mutations on both viral replication and MHC-I binding affinity are among the determinants of CTL escape. Mutations in Gag epitopes presented by protective MHC-I alleles are associated with significantly higher fitness cost and lower reductions in binding affinity with respect to MHC-I. A linear regression model accounting for the effect of mutations on both viral replicative capacity and MHC-I binding can explain the protective efficacy of MHC-I alleles. Finally, we found a consistent pattern in the evolution of Gag epitopes in long-term nonprogressors versus progressors. Overall, our results suggest that certain protective MHC-I alleles allow superior control of HIV-1 by targeting epitopes where mutations typically incur high fitness costs and small reductions in MHC-I binding affinity. IMPORTANCE Understanding the mechanism of viral control achieved in long-term nonprogressors with protective HLA alleles provides insights for developing functional cure of HIV infection. Through the characterization of CTL escape mutations in infected persons, previous researchers hypothesized that protective alleles target epitopes where escape mutations significantly reduce viral replicative capacity. How-ever, these studies were usually limited to a few mutations observed in vivo. Here we utilized our recently developed high-throughput fitness profiling method to quantitatively measure the fitness of mutations across the entirety of HIV-1 Gag. The data enabled us to integrate the results with in silico prediction of MHC-peptide binding affinity and analysis of intraperson virus evolution to systematically determine the differences in CTL escape mutations between epitopes targeted by protective HLA alleles and those targeted by nonprotective HLA alleles. We observed that the effects of Gag epitope mutations on HIV replicative fitness and MHC-I binding affinity are among the major determinants of CTL escape.-
dc.languageeng-
dc.relation.ispartofmBio-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectHIV-I-
dc.subjectMHC binding prediction-
dc.subjectIntrapatient viral evolution-
dc.subjectHigh-throughput fitness profiling-
dc.subjectGag epitopes-
dc.subjectCTL escape-
dc.titleEffects of mutations on replicative fitness and major histocompatibility complex class I binding affinity are among the determinants underlying Cytotoxic-T-Lymphocyte escape of HIV-1 Gag epitopes-
dc.typeArticle-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1128/mBio.01050-17-
dc.identifier.pmid29184023-
dc.identifier.pmcidPMC5705913-
dc.identifier.scopuseid_2-s2.0-85039899709-
dc.identifier.volume8-
dc.identifier.issue6-
dc.identifier.spagearticle no. e01050-17-
dc.identifier.epagearticle no. e01050-17-
dc.identifier.eissn2150-7511-
dc.identifier.isiWOS:000418889500004-
dc.identifier.issnl2150-7511-

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