Distinct genetic architectures and environmental factors associate with host response to the γ2-herpesvirus infections

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr Virus (EBV) establish lifelong infections and are associated with malignancies. Striking geographic variation in incidence and the fact that virus alone is insufficient to cause disease, suggests other co-factors are involved. Here we present epidemiological analysis and genome-wide association study (GWAS) in 4365 individuals from an African population cohort, to assess the influence of host genetic and non-genetic factors on virus antibody responses. EBV/KSHV co-infection (OR = 5.71(1.58-7.12)), HIV positivity (OR = 2.22(1.32-3.73)) and living in a more rural area (OR = 1.38(1.01-1.89)) are strongly associated with immunogenicity. GWAS reveals associations with KSHV antibody response in the HLA-B/C region (p = 6.64 × 10 −09). For EBV, associations are identified for VCA (rs71542439, p = 1.15 × 10 −12). Human leucocyte antigen (HLA) and trans-ancestry fine-mapping substantiate that distinct variants in HLA-DQA1 (p = 5.24 × 10 −44) are driving associations for EBNA-1 in Africa. This study highlights complex interactions between KSHV and EBV, in addition to distinct genetic architectures resulting in important differences in pathogenesis and transmission.

Roles of Lytic Viral Replication and Co-Infections in the Oncogenesis and Immune Control of the Epstein–Barr Virus

“…More recently, it was also found that EBV infection supports persistent KSHV infection both in humanized mice [ 131 , 134 ] and in vitro [ 130 , 135 ]. Consistent with these findings are the observations that KSHV is usually not found without EBV co-infection in African children [ 136 , 137 ], and that the monkey orthologs of these viruses can be co-transmitted in macaques [ 138 ]. Moreover, co-infection of EBV with KSHV in humanized mice causes increased lymphoma formation, and the emerging lymphomas display some features of plasma cell differentiation [ 131 , 134 ] which is characteristic for PELs [ 133 ].…”

Natural Killer Cell Responses during Human γ-Herpesvirus Infections

“…Such coinfection can also be observed in primary effusion lymphoma (PEL), a B cell tumor in which KSHV genome maintenance is compromised when EBV is deleted [21,22]. Furthermore, epidemiologically, KSHV infection is associated with EBV infection in African children [23,24]. It remains unclear under which circumstances KSHV infects the endothelial cells from which Kaposi sarcoma originates [2,25].…”

Modification of EBV Associated Lymphomagenesis and Its Immune Control by Co-Infections and Genetics in Humanized Mice

“…Both EBV and KSHV are found in the tumor cells of 90% of primary effusion lymphomas (PELs) ( 10 ). Moreover, KSHV infection seems to benefit from EBV co-infection for persistence ( 47 , 86 – 88 ). Humanized mice that are infected with both KSHV and EBV develop B cell lymphomas with higher incidence ( 47 ).…”