The contribution of host genetics and environmental variation to immune response in gamma-herpesvirus infections

Abstract

Background: The gamma-herpesviruses, Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr Virus (EBV) establish life-long infections in humans and have been associated with a variety of malignancies. While EBV is ubiquitous, KSHV displays striking geographic variation with highest prevalence in sub-Saharan Africa. Although both viruses have been studied extensively, how host genetic and environmental variation influences infection traits is largely unknown, particularly in Africa. Methods & Materials: We used socio-demographic, clinical and host genotype data of 4365 individuals in an African population, to assess the influence of environmental factors and host genetics on KSHV and EBV IgG antibody response levels. We performed multivariate regression modelling to assess environmental predictors of IgG levels. We performed genome-wide association analysis (GWAS) of IgG traits across ∼17 million variants using a combined approach including array genotyping, whole-genome sequencing and imputation to a panel with African sequence data to extensively genetic capture variation in the context of the environment. Results: We identified a high burden of KSHV and EBV (91%) infections along with co-infection with up to four pathogens. HIV positivity (βKSHV = −0.36(−0.43,−0.29), βEBV = 0.35 (0.28,0.42)), EBV/KSHV co-infection (βKSHV = 0.66 (0.62, 0.71), βEBV = 0.25 (0.21,0.28)) along with educational attainment (βKSHV = −0.22 (−0.30,−0.14), βEBV = 0.12 (0.03,0.21)) and urbanicity attainment (βKSHV = −0.10 (−0.15,−0.05), βEBV = 0.11 (0.05,0.16)), were strong determinants of humoral immunity. GWAS revealed the HLA locus as the strongest determinant of variation in antibody response however, much stronger associations were observed for EBV (HLA-DQA1, p = 5.24 × 10−33) compared to KSHV (HLA-B/C, p = 4.59 × 10−08). Conclusion: Despite being from the same family of viruses, our study highlights distinct phenotypic and genetic architectures of KSHV and EBV traits in addition to complex interactions between the two, suggestive of important differences in pathogenesis and transmission. Particularly as Uganda sustains such a high transmission of KSHV compared to the rest of the world, these insights are invaluable for informing intervention and control measures of these viruses.