The influence of human genetic variation on Epstein–Barr virus sequence diversity

Abstract

Epstein–Barr virus (EBV) is one of the most common viruses latently infecting humans. Little is known about the impact of human genetic variation on the large inter-individual differences observed in response to EBV infection. To search for a potential imprint of host genomic variation on the EBV sequence, we jointly analyzed paired viral and human genomic data from 268 HIV-coinfected individuals with CD4 + T cell count < 200/mm3 and elevated EBV viremia. We hypothesized that the reactivated virus circulating in these patients could carry sequence variants acquired during primary EBV infection, thereby providing a snapshot of early adaptation to the pressure exerted on EBV by the individual immune response. We searched for associations between host and pathogen genetic variants, taking into account human and EBV population structure. Our analyses revealed significant associations between human and EBV sequence variation. Three polymorphic regions in the human genome were found to be associated with EBV variation: one at the amino acid level (BRLF1:p.Lys316Glu); and two at the gene level (burden testing of rare variants in BALF5 and BBRF1). Our findings confirm that jointly analyzing host and pathogen genomes can identify sites of genomic interactions, which could help dissect pathogenic mechanisms and suggest new therapeutic avenues.

Genome-wide host-pathogen analyses reveal genetic interaction points in tuberculosis disease

“…One of the first studies reported associations between human genetic variants and 48 HIV-1 amino acid variants in 1071 HIV-infected patients, where all associated host SNPs mapped to the HLA class I region and none of the viral amino acids mapped to known sites of major antiretroviral drug resistance mutations 25 . Similarly, a study of Epstein-Barr virus found significant associations between human and viral sequence variation, involving three polymorphic regions in the human genome, including SNPs on chromosome 7, and a variant in the BRLF1 gene of the virus 27 . Host-pathogen co-evolution has also been proposed as an interaction mechanism for TB, however, the diversity found among Mtb differs from the viral setting.…”

“…Host-pathogen interaction genomics, using genome-to-genome analytical approaches, has already begun to be used to identify pathogenic mechanisms associated with other diseases, including HIV 25 , hepatitis C virus infection 26 and Epstein-Barr virus 27 . However, these approaches have not been applied to TB, where genetic studies have predominantly considered human and Mtb genomes separately.…”

Environmental Factors for Epstein-Barr Virus Reactivation in a High-Risk Area of Nasopharyngeal Carcinoma: A Population-Based Study

“…By contrast, recent genomic analyses showed that host and viral genetic variation may affect EBV lytic reactivation. A study that analyzed paired EB viral and human genomic data from 268 human immunodeficiency virus-coinfected individuals reported significant associations between 25 human single-nucleotide polymorphisms and viral variants mapping to 3 EBV regions including BALF5 , BBRF1 , and BRLF1 [ 34 ]. These genes are involved in controlling EBV reactivation from latency and regulation of viral deoxyribonucleic acid (DNA) replication.…”

The role of Epstein–Barr virus in nasopharyngeal carcinoma

“…Furthermore, the majority of studies on EBV genotyping were limited to certain regions. Moreover, it was reported that EBV sequence variation is associated with host sequence variants, hence, joint analyses of host and viral genome variation would help decipher the pathogenesis of NPC and identify novel diagnostic and therapeutic targets ( Rüeger et al, 2021 ). Studies recruiting larger samples involving individuals with different conditions from different ethnic groups and geographical regions are needed to determine the exact association of EBV strains with the geographical distribution and development of the disease.…”