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Immunogenetic determinants of heterosexual HIV-1 transmission: key findings and lessons from two distinct African cohorts

Abstract

Immunogenetic studies in the past three decades have uncovered a broad range of human genetic factors that seem to influence heterosexual HIV-1 transmission in one way or another. In our own work that jointly evaluated both genetic and nongenetic factors in two African cohorts of cohabiting, HIV-1-discordant couples (donor and recipient pairs) at risk of transmission during quarterly follow-up intervals, relatively consistent findings have been seen with three loci (IL19, HLA-A, and HLA-B), although the effect size (i.e., odds ratio or hazards ratio) of each specific variant was quite modest. These studies offered two critical lessons that should benefit future research on sexually transmitted infections. First, in donor partners, immunogenetic factors (e.g., HLA-B*57 and HLA-A*36:01) that operate directly through HIV-1 viral load or indirectly through genital coinfections are equally important. Second, thousands of single-nucleotide polymorphisms previously recognized as “causal” factors for human autoimmune disorders did not appear to make much difference, which is somewhat puzzling as these variants are predicted or known to influence the expression of many immune response genes. Replicating these observations in additional cohorts is no longer feasible as the field has shifted its focus to early diagnosis, universal treatment, and active management of comorbidities.

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Fig. 1: Several scenarios in the setting of heterosexual HIV-1 transmission among discordant couples.
Fig. 2: Kaplan–Meier curves showing the impact of HIV-1 viral load (VL) in donor/index partners on heterosexual HIV-1 transmission among 420 HIV-1 discordant Zambian couples with longitudinal follow-up.
Fig. 3: Kaplan–Meier curves showing the impact of HLA-A*36:01 in donor/index partners on heterosexual HIV-1 transmission and genital ulcer/inflammation (GUI) during longitudinal follow-up.
Fig. 4: A 3D graph showing the clustering of subjects from three countries.

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Acknowledgements

The original data included in this review came primarily from an R01 project (AI071906) funded by the National Institute of Allergy and Infectious Disease, with further funding from R01-AI64060. Unpublished genomics data for African–Americans and European Americans came from a third project (R21-AG051309). I am grateful to Dr. Richard A. Kaslow, Dr. Susan Allen, and Dr. Eric Hunter for their leadership during these projects. Members of the Rwanda–Zambia HIV-1 Research Group were essential to patient enrollment and data management. Refinements of earlier findings based on updated datasets were made possible by statistical models prepared by Mr. Xuelin Li, Dr. Heather A. Prentice, and Dr. Howard Wiener.

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Tang, J. Immunogenetic determinants of heterosexual HIV-1 transmission: key findings and lessons from two distinct African cohorts. Genes Immun (2021). https://doi.org/10.1038/s41435-021-00130-y

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