HLA-B∗46 associates with rapid HIV disease progression in Asian cohorts and prominent differences in NK cell phenotype

Human leukocyte antigen (HLA) alleles have been linked to HIV disease progression and attributed to differences in cytotoxic T lymphocyte (CTL) epitope representation. These findings are largely based on treatment-naive individuals of European and African ancestry. We assessed HLA associations with...

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Published in:Cell host & microbe 2022-08, Vol.30 (8), p.1173-1185.e8
Main Authors: Li, Shuying S., Hickey, Andrew, Shangguan, Shida, Ehrenberg, Philip K., Geretz, Aviva, Butler, Lauryn, Kundu, Gautam, Apps, Richard, Creegan, Matthew, Clifford, Robert J., Pinyakorn, Suteeraporn, Eller, Leigh Anne, Luechai, Pikunchai, Gilbert, Peter B., Holtz, Timothy H., Chitwarakorn, Anupong, Sacdalan, Carlo, Kroon, Eugène, Phanuphak, Nittaya, de Souza, Mark, Ananworanich, Jintanat, O'Connell, Robert J., Robb, Merlin L., Michael, Nelson L., Vasan, Sandhya, Thomas, Rasmi
Format: Article
Language:English
Subjects:
acute HIV infection
CD4 counts
CITE-seq
cytotoxic T lymphocytes
HLA
KIR
NK cells
RNA-seq
Thailand
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Summary:Human leukocyte antigen (HLA) alleles have been linked to HIV disease progression and attributed to differences in cytotoxic T lymphocyte (CTL) epitope representation. These findings are largely based on treatment-naive individuals of European and African ancestry. We assessed HLA associations with HIV-1 outcomes in 1,318 individuals from Thailand and found HLA-B∗46:01 (B∗46) associated with accelerated disease in three independent cohorts. B∗46 had no detectable effect on HIV-specific T cell responses, but this allele is unusual in containing an HLA-C epitope that binds inhibitory receptors on natural killer (NK) cells. Unbiased transcriptomic screens showed increased NK cell activation in people with HIV, without B∗46, and simultaneous single-cell profiling of surface proteins and transcriptomes revealed a NK cell subset primed for increased responses in the absence of B∗46. These findings support a role for NK cells in HIV pathogenesis, revealed by the unique properties of the B∗46 allele common only in Asia. [Display omitted] •HLA-B∗46 associates with accelerated HIV disease progression and reduced CD4 counts•HLA-B∗46 is unique in conferring unusual stimulation of NK cell receptors•In people without B∗46, CITE-seq reveals subsets of NK cells with distinct phenotypes•These differences in innate immunity may confer protection upon HIV infection Li et al. show that B∗46, the most frequent HLA-B allele in Thailand, is associated with HIV disease progression in three independent cohorts. This may result from differences in NK cell populations, specifically a subset with an activated phenotype that was found to be absent in people with HLA-B∗46.
ISSN:1931-3128
1934-6069
DOI:10.1016/j.chom.2022.06.005