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Host genetics and immune control of HIV-1 infection: fine mapping for the extended human MHC region in an African cohort

Genes & Immunity volume 15, pages 275–281 (2014)Cite this article

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Abstract

Multiple major histocompatibility complex (MHC) loci encoding human leukocyte antigens (HLA) have allelic variants unequivocally associated with differential immune control of HIV-1 infection. Fine mapping based on single nucleotide polymorphisms (SNPs) in the extended MHC (xMHC) region is expected to reveal causal or novel factors and to justify a search for functional mechanisms. We have tested the utility of a custom fine-mapping platform (the ImmunoChip) for 172 HIV-1 seroconverters (SCs) and 449 seroprevalent individuals (SPs) from Lusaka, Zambia, with a focus on more than 6400 informative xMHC SNPs. When conditioned on HLA and nongenetic factors previously associated with HIV-1 viral load (VL) in the study cohort, penalized approaches (HyperLasso models) identified an intergenic SNP (rs3094626 between RPP21 and HLA-E) and an intronic SNP (rs3134931 in NOTCH4) as novel correlates of early set-point VL in SCs. The minor allele of rs2857114 (downstream from HLA-DOB) was an unfavorable factor in SPs. Joint models based on demographic features, HLA alleles and the newly identified SNP variants could explain 29% and 15% of VL variance in SCs and SPs, respectively. These findings and bioinformatics strongly suggest that both classic and nonclassic MHC genes deserve further investigation, especially in Africans with relatively short haplotype blocks.

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Acknowledgements

This work was supported by multiple grants, including R01 AI071906 (to RAK and JT) and R01 AI064060 (to EH) from the National Institute of Allergy and Infectious Diseases (NIAID). We are grateful to several associates, especially Ilene Brill, Paul Farmer, Travis Porter and Wei Song, for their contribution to data management and genotyping.

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Author notes

  1. H A Prentice

    Present address: 8Current address: US Military HIV Research Program, Silver Spring, MD 20850, USA.,

  2. R A Kaslow

    Present address: 9Current address: Department of Veterans Affairs, Washington, DC 20420, USA.,

Authors and Affiliations

  1. Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA

    H A Prentice, D He, E E Brown, R A Kaslow & J Tang

  2. Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA

    N M Pajewski

  3. Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA

    K Zhang

  4. Zambia-Emory HIV-1 Research Project, Lusaka, Zambia

    W Kilembe & S Allen

  5. Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA

    S Allen

  6. Emory Vaccine Center, Emory University, Atlanta, GA, USA

    E Hunter

  7. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    J Tang

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Prentice, H., Pajewski, N., He, D. et al. Host genetics and immune control of HIV-1 infection: fine mapping for the extended human MHC region in an African cohort. Genes Immun 15, 275–281 (2014). https://doi.org/10.1038/gene.2014.16

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