Co-operative additive effects between HLA alleles in control of HIV-1
Background HLA class I genotype is a major determinant of the outcome of HIV infection, and the impact of certain alleles on HIV disease outcome is well studied. Recent studies have demonstrated that certain HLA class I alleles that are in linkage disequilibrium, such as HLA-A*74 and HLA-B*57, appea...
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Public Library of Science
2012
|
| _version_ | 1826259140302864384 |
|---|---|
| author | Matthews, P Listgarten, J Carlson, J Payne, R Huang, K Frater, J Goedhals, D Steyn, D Van Vuuren, C Paioni, P Jooste, P Ogwu, A Shapiro, R Mncube, Z Ndung'U, T Walker, B Heckerman, D Goulder, P |
| author_facet | Matthews, P Listgarten, J Carlson, J Payne, R Huang, K Frater, J Goedhals, D Steyn, D Van Vuuren, C Paioni, P Jooste, P Ogwu, A Shapiro, R Mncube, Z Ndung'U, T Walker, B Heckerman, D Goulder, P |
| author_sort | Matthews, P |
| collection | OXFORD |
| description | Background HLA class I genotype is a major determinant of the outcome of HIV infection, and the impact of certain alleles on HIV disease outcome is well studied. Recent studies have demonstrated that certain HLA class I alleles that are in linkage disequilibrium, such as HLA-A*74 and HLA-B*57, appear to function co-operatively to result in greater immune control of HIV than mediated by either single allele alone. We here investigate the extent to which HLA alleles - irrespective of linkage disequilibrium - function co-operatively. Methodology/Principal Findings We here refined a computational approach to the analysis of >2000 subjects infected with C-clade HIV first to discern the individual effect of each allele on disease control, and second to identify pairs of alleles that mediate ‘co-operative additive’ effects, either to improve disease suppression or to contribute to immunological failure. We identified six pairs of HLA class I alleles that have a co-operative additive effect in mediating HIV disease control and four hazardous pairs of alleles that, occurring together, are predictive of worse disease outcomes (q<0.05 in each case). We developed a novel ‘sharing score’ to quantify the breadth of CD8+ T cell responses made by pairs of HLA alleles across the HIV proteome, and used this to demonstrate that successful viraemic suppression correlates with breadth of unique CD8+ T cell responses (p = 0.03). Conclusions/Significance These results identify co-operative effects between HLA Class I alleles in the control of HIV-1 in an extended Southern African cohort, and underline complementarity and breadth of the CD8+ T cell targeting as one potential mechanism for this effect. |
| first_indexed | 2024-03-06T18:45:09Z |
| format | Journal article |
| id | oxford-uuid:0e3ec0cb-e158-4144-b7da-be1e29d48d3e |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:45:09Z |
| publishDate | 2012 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:0e3ec0cb-e158-4144-b7da-be1e29d48d3e2022-03-26T09:44:56ZCo-operative additive effects between HLA alleles in control of HIV-1Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:0e3ec0cb-e158-4144-b7da-be1e29d48d3eEnglishSymplectic Elements at OxfordPublic Library of Science2012Matthews, PListgarten, JCarlson, JPayne, RHuang, KFrater, JGoedhals, DSteyn, DVan Vuuren, CPaioni, PJooste, POgwu, AShapiro, RMncube, ZNdung'U, TWalker, BHeckerman, DGoulder, PBackground HLA class I genotype is a major determinant of the outcome of HIV infection, and the impact of certain alleles on HIV disease outcome is well studied. Recent studies have demonstrated that certain HLA class I alleles that are in linkage disequilibrium, such as HLA-A*74 and HLA-B*57, appear to function co-operatively to result in greater immune control of HIV than mediated by either single allele alone. We here investigate the extent to which HLA alleles - irrespective of linkage disequilibrium - function co-operatively. Methodology/Principal Findings We here refined a computational approach to the analysis of >2000 subjects infected with C-clade HIV first to discern the individual effect of each allele on disease control, and second to identify pairs of alleles that mediate ‘co-operative additive’ effects, either to improve disease suppression or to contribute to immunological failure. We identified six pairs of HLA class I alleles that have a co-operative additive effect in mediating HIV disease control and four hazardous pairs of alleles that, occurring together, are predictive of worse disease outcomes (q<0.05 in each case). We developed a novel ‘sharing score’ to quantify the breadth of CD8+ T cell responses made by pairs of HLA alleles across the HIV proteome, and used this to demonstrate that successful viraemic suppression correlates with breadth of unique CD8+ T cell responses (p = 0.03). Conclusions/Significance These results identify co-operative effects between HLA Class I alleles in the control of HIV-1 in an extended Southern African cohort, and underline complementarity and breadth of the CD8+ T cell targeting as one potential mechanism for this effect. |
| spellingShingle | Matthews, P Listgarten, J Carlson, J Payne, R Huang, K Frater, J Goedhals, D Steyn, D Van Vuuren, C Paioni, P Jooste, P Ogwu, A Shapiro, R Mncube, Z Ndung'U, T Walker, B Heckerman, D Goulder, P Co-operative additive effects between HLA alleles in control of HIV-1 |
| title | Co-operative additive effects between HLA alleles in control of HIV-1 |
| title_full | Co-operative additive effects between HLA alleles in control of HIV-1 |
| title_fullStr | Co-operative additive effects between HLA alleles in control of HIV-1 |
| title_full_unstemmed | Co-operative additive effects between HLA alleles in control of HIV-1 |
| title_short | Co-operative additive effects between HLA alleles in control of HIV-1 |
| title_sort | co operative additive effects between hla alleles in control of hiv 1 |
| work_keys_str_mv | AT matthewsp cooperativeadditiveeffectsbetweenhlaallelesincontrolofhiv1 AT listgartenj cooperativeadditiveeffectsbetweenhlaallelesincontrolofhiv1 AT carlsonj cooperativeadditiveeffectsbetweenhlaallelesincontrolofhiv1 AT payner cooperativeadditiveeffectsbetweenhlaallelesincontrolofhiv1 AT huangk cooperativeadditiveeffectsbetweenhlaallelesincontrolofhiv1 AT fraterj cooperativeadditiveeffectsbetweenhlaallelesincontrolofhiv1 AT goedhalsd cooperativeadditiveeffectsbetweenhlaallelesincontrolofhiv1 AT steynd cooperativeadditiveeffectsbetweenhlaallelesincontrolofhiv1 AT vanvuurenc cooperativeadditiveeffectsbetweenhlaallelesincontrolofhiv1 AT paionip cooperativeadditiveeffectsbetweenhlaallelesincontrolofhiv1 AT joostep cooperativeadditiveeffectsbetweenhlaallelesincontrolofhiv1 AT ogwua cooperativeadditiveeffectsbetweenhlaallelesincontrolofhiv1 AT shapiror cooperativeadditiveeffectsbetweenhlaallelesincontrolofhiv1 AT mncubez cooperativeadditiveeffectsbetweenhlaallelesincontrolofhiv1 AT ndungut cooperativeadditiveeffectsbetweenhlaallelesincontrolofhiv1 AT walkerb cooperativeadditiveeffectsbetweenhlaallelesincontrolofhiv1 AT heckermand cooperativeadditiveeffectsbetweenhlaallelesincontrolofhiv1 AT goulderp cooperativeadditiveeffectsbetweenhlaallelesincontrolofhiv1 |