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
ABSTRACT 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...
Guardado en:
| Autores principales: | , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
American Society for Microbiology
2017
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/85c05c9d6e2845998b33493d2d33d8ed |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:85c05c9d6e2845998b33493d2d33d8ed |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:85c05c9d6e2845998b33493d2d33d8ed2021-11-15T15:51:56ZEffects 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 Epitopes10.1128/mBio.01050-172150-7511https://doaj.org/article/85c05c9d6e2845998b33493d2d33d8ed2017-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01050-17https://doaj.org/toc/2150-7511ABSTRACT 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. However, 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.Yushen DuTian-Hao ZhangLei DaiXiaojuan ZhengAleksandr M. GorinJohn OishiTing-Ting WuJanice M. YoshizawaXinmin LiOtto O. YangOtoniel Martinez-MazaRoger DetelsRen SunAmerican Society for MicrobiologyarticleCTL escapeGag epitopesHIV-Ihigh-throughput fitness profilingMHC binding predictionintrapatient viral evolutionMicrobiologyQR1-502ENmBio, Vol 8, Iss 6 (2017) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
CTL escape Gag epitopes HIV-I high-throughput fitness profiling MHC binding prediction intrapatient viral evolution Microbiology QR1-502 |
| spellingShingle |
CTL escape Gag epitopes HIV-I high-throughput fitness profiling MHC binding prediction intrapatient viral evolution Microbiology QR1-502 Yushen Du Tian-Hao Zhang Lei Dai Xiaojuan Zheng Aleksandr M. Gorin John Oishi Ting-Ting Wu Janice M. Yoshizawa Xinmin Li Otto O. Yang Otoniel Martinez-Maza Roger Detels Ren Sun 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 |
| description |
ABSTRACT 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. However, 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. |
| format |
article |
| author |
Yushen Du Tian-Hao Zhang Lei Dai Xiaojuan Zheng Aleksandr M. Gorin John Oishi Ting-Ting Wu Janice M. Yoshizawa Xinmin Li Otto O. Yang Otoniel Martinez-Maza Roger Detels Ren Sun |
| author_facet |
Yushen Du Tian-Hao Zhang Lei Dai Xiaojuan Zheng Aleksandr M. Gorin John Oishi Ting-Ting Wu Janice M. Yoshizawa Xinmin Li Otto O. Yang Otoniel Martinez-Maza Roger Detels Ren Sun |
| author_sort |
Yushen Du |
| title |
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 |
| title_short |
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 |
| title_full |
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 |
| title_fullStr |
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 |
| title_full_unstemmed |
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 |
| title_sort |
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 |
| publisher |
American Society for Microbiology |
| publishDate |
2017 |
| url |
https://doaj.org/article/85c05c9d6e2845998b33493d2d33d8ed |
| work_keys_str_mv |
AT yushendu effectsofmutationsonreplicativefitnessandmajorhistocompatibilitycomplexclassibindingaffinityareamongthedeterminantsunderlyingcytotoxictlymphocyteescapeofhiv1gagepitopes AT tianhaozhang effectsofmutationsonreplicativefitnessandmajorhistocompatibilitycomplexclassibindingaffinityareamongthedeterminantsunderlyingcytotoxictlymphocyteescapeofhiv1gagepitopes AT leidai effectsofmutationsonreplicativefitnessandmajorhistocompatibilitycomplexclassibindingaffinityareamongthedeterminantsunderlyingcytotoxictlymphocyteescapeofhiv1gagepitopes AT xiaojuanzheng effectsofmutationsonreplicativefitnessandmajorhistocompatibilitycomplexclassibindingaffinityareamongthedeterminantsunderlyingcytotoxictlymphocyteescapeofhiv1gagepitopes AT aleksandrmgorin effectsofmutationsonreplicativefitnessandmajorhistocompatibilitycomplexclassibindingaffinityareamongthedeterminantsunderlyingcytotoxictlymphocyteescapeofhiv1gagepitopes AT johnoishi effectsofmutationsonreplicativefitnessandmajorhistocompatibilitycomplexclassibindingaffinityareamongthedeterminantsunderlyingcytotoxictlymphocyteescapeofhiv1gagepitopes AT tingtingwu effectsofmutationsonreplicativefitnessandmajorhistocompatibilitycomplexclassibindingaffinityareamongthedeterminantsunderlyingcytotoxictlymphocyteescapeofhiv1gagepitopes AT janicemyoshizawa effectsofmutationsonreplicativefitnessandmajorhistocompatibilitycomplexclassibindingaffinityareamongthedeterminantsunderlyingcytotoxictlymphocyteescapeofhiv1gagepitopes AT xinminli effectsofmutationsonreplicativefitnessandmajorhistocompatibilitycomplexclassibindingaffinityareamongthedeterminantsunderlyingcytotoxictlymphocyteescapeofhiv1gagepitopes AT ottooyang effectsofmutationsonreplicativefitnessandmajorhistocompatibilitycomplexclassibindingaffinityareamongthedeterminantsunderlyingcytotoxictlymphocyteescapeofhiv1gagepitopes AT otonielmartinezmaza effectsofmutationsonreplicativefitnessandmajorhistocompatibilitycomplexclassibindingaffinityareamongthedeterminantsunderlyingcytotoxictlymphocyteescapeofhiv1gagepitopes AT rogerdetels effectsofmutationsonreplicativefitnessandmajorhistocompatibilitycomplexclassibindingaffinityareamongthedeterminantsunderlyingcytotoxictlymphocyteescapeofhiv1gagepitopes AT rensun effectsofmutationsonreplicativefitnessandmajorhistocompatibilitycomplexclassibindingaffinityareamongthedeterminantsunderlyingcytotoxictlymphocyteescapeofhiv1gagepitopes |
| _version_ |
1718427287205969920 |