Associations of functional human leucocyte antigen class I groups with HIV viral load in a heterogeneous cohort
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Associations of functional human leucocyte antigen class I groups with HIV viral load in a heterogeneous cohort. / Zucco, Adrian G.; Bennedbæk, Marc; Ekenberg, Christina; Gabrielaite, Migle; Leung, Preston; Polizzotto, Mark N; Kan, Virginia; Murray, Daniel D; Lundgren, Jens D; MacPherson, Cameron R.; INSIGHT START Study Group.
In: AIDS, Vol. 37, No. 11, 2023, p. 1643-1650.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Associations of functional human leucocyte antigen class I groups with HIV viral load in a heterogeneous cohort
AU - Zucco, Adrian G.
AU - Bennedbæk, Marc
AU - Ekenberg, Christina
AU - Gabrielaite, Migle
AU - Leung, Preston
AU - Polizzotto, Mark N
AU - Kan, Virginia
AU - Murray, Daniel D
AU - Lundgren, Jens D
AU - MacPherson, Cameron R.
AU - INSIGHT START Study Group
N1 - Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.
PY - 2023
Y1 - 2023
N2 - OBJECTIVE: Human leucocyte antigen (HLA) class I alleles are the main host genetic factors involved in controlling HIV-1 viral load (VL). Nevertheless, HLA diversity has proven a significant challenge in association studies. We assessed how accounting for binding affinities of HLA class I alleles to HIV-1 peptides facilitate association testing of HLA with HIV-1 VL in a heterogeneous cohort.DESIGN: Cohort from the Strategic Timing of AntiRetroviral Treatment (START) study.METHODS: We imputed HLA class I alleles from host genetic data (2546 HIV+ participants) and sampled immunopeptidomes from 2079 host-paired viral genomes (targeted amplicon sequencing). We predicted HLA class I binding affinities to HIV-1 and unspecific peptides, grouping alleles into functional clusters through consensus clustering. These functional HLA class I clusters were used to test associations with HIV VL.RESULTS: We identified four clades totaling 30 HLA alleles accounting for 11.4% variability in VL. We highlight HLA-B∗57:01 and B∗57:03 as functionally similar but yet overrepresented in distinct ethnic groups, showing when combined a protective association with HIV+ VL (log, β -0.25; adj. P-value < 0.05). We further demonstrate only a slight power reduction when using unspecific immunopeptidomes, facilitating the use of the inferred functional HLA groups in other studies.CONCLUSION: The outlined computational approach provides a robust and efficient way to incorporate HLA function and peptide diversity, aiding clinical association studies in heterogeneous cohorts. To facilitate access to the proposed methods and results we provide an interactive application for exploring data.
AB - OBJECTIVE: Human leucocyte antigen (HLA) class I alleles are the main host genetic factors involved in controlling HIV-1 viral load (VL). Nevertheless, HLA diversity has proven a significant challenge in association studies. We assessed how accounting for binding affinities of HLA class I alleles to HIV-1 peptides facilitate association testing of HLA with HIV-1 VL in a heterogeneous cohort.DESIGN: Cohort from the Strategic Timing of AntiRetroviral Treatment (START) study.METHODS: We imputed HLA class I alleles from host genetic data (2546 HIV+ participants) and sampled immunopeptidomes from 2079 host-paired viral genomes (targeted amplicon sequencing). We predicted HLA class I binding affinities to HIV-1 and unspecific peptides, grouping alleles into functional clusters through consensus clustering. These functional HLA class I clusters were used to test associations with HIV VL.RESULTS: We identified four clades totaling 30 HLA alleles accounting for 11.4% variability in VL. We highlight HLA-B∗57:01 and B∗57:03 as functionally similar but yet overrepresented in distinct ethnic groups, showing when combined a protective association with HIV+ VL (log, β -0.25; adj. P-value < 0.05). We further demonstrate only a slight power reduction when using unspecific immunopeptidomes, facilitating the use of the inferred functional HLA groups in other studies.CONCLUSION: The outlined computational approach provides a robust and efficient way to incorporate HLA function and peptide diversity, aiding clinical association studies in heterogeneous cohorts. To facilitate access to the proposed methods and results we provide an interactive application for exploring data.
KW - Humans
KW - Viral Load
KW - HIV Infections/drug therapy
KW - Histocompatibility Antigens Class I/genetics
KW - HLA-B Antigens/genetics
KW - HIV Seropositivity
KW - HIV-1/genetics
KW - Alleles
U2 - 10.1097/QAD.0000000000003557
DO - 10.1097/QAD.0000000000003557
M3 - Journal article
C2 - 37534724
VL - 37
SP - 1643
EP - 1650
JO - AIDS
JF - AIDS
SN - 1350-2840
IS - 11
ER -
ID: 361442254