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HLA-DPB1 and Epstein-Barr virus gp42 protein jointly contribute to the development of Hodgkin lymphoma

ABSTRACT:

Background

Epstein-Barr virus (EBV) glycoprotein 42 (gp42) enters B lymphocytes by binding to the human leukocyte antigen II (HLA-II) on their surface, in a process involving other EBV proteins (e.g., gH/gL and gp350). From a latent state of infection, the virus may reactivate and enter into a rapid proliferation phase, which enables the further entry of EBV into B lymphocytes and epithelial cells, leading to tumor development. EBV is an oncogenic virus associated with Hodgkin lymphoma (HL), and gp42 is a key protein in EBV infection of B lymphocytes. However, the exact binding pattern and capacity of gp42 are unclear.

Methods

The patterns and morphologies of gp42 binding to HLA-DPB1 were obtained through molecular dynamics simulation. The binding efficiency of gp42 and HLA-DPB1 was verified by plasmid construction and flow cytometry.

Results

The β-chain of HLA-DPB1 and the α-chain of gp42 formed a hydrogen-bonded complex, which was a hydrophilic protein with a resolution of 3.25. The binding efficiency between HLA-DPB1 and gp42 reached its peak (range, 26–31.3%) at a gp42 protein concentration of 80 µg.

Conclusions

We can inhibit the binding of gp42 to HLA-DPB1 by reducing the concentration of gp42. In the subsequent experiments, we will verify whether the binding of gp42 to HLA-DPB1 can be prevented by breaking hydrogen bonds and destroying hydrophilicity. These data may provide certain reference value for the development and treatment of Hodgkin’s lymphoma.

SUBMITTER: Li H

PROVIDER: S-EPMC8798132 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAccumulating evidence suggests that risk factors for classical Hodgkin lymphoma (cHL) differ by tumor Epstein-Barr virus (EBV) status. This potential etiological heterogeneity is not recognized in current disease classification.MethodsWe conducted a genome-wide association study of 1200 cHL patients and 6417 control subjects, with validation in an independent replication series, to identify common genetic variants associated with total cHL and subtypes defined by tumor EBV status. Multiple logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) assuming a log-additive genetic model for the variants. All statistical tests were two-sided.ResultsTwo novel loci associated with total cHL irrespective of EBV status were identified in the major histocompatibility complex region; one resides adjacent to MICB (rs2248462: OR = 0.61, 95% CI = 0.53 to 0.69, P = 1.3 × 10(-13)) and the other at HLA-DRA (rs2395185: OR = 0.56, 95% CI = 0.50 to 0.62, P = 8.3 × 10(-25)) with both results confirmed in an independent replication series. Consistent with previous reports, associations were found between EBV-positive cHL and genetic variants within the class I region (rs2734986, HLA-A: OR = 2.45, 95% CI = 2.00 to 3.00, P = 1.2 × 10(-15); rs6904029, HCG9: OR = 0.46, 95% CI = 0.36 to 0.59, P = 5.5 × 10(-10)) and between EBV-negative cHL and rs6903608 within the class II region (rs6903608, HLA-DRA: OR = 2.08, 95% CI = 1.84 to 2.35, P = 6.1 × 10(-31)). The association between rs6903608 and EBV-negative cHL was confined to the nodular sclerosis histological subtype. Evidence for an association between EBV-negative cHL and rs20541 (5q31, IL13: OR = 1.53, 95% CI = 1.32 to 1.76, P = 5.4 x 10(-9)), a variant previously linked to psoriasis and asthma, was observed; however, the evidence for replication was less clear. Notably, one additional psoriasis-associated variant, rs27524 (5q15, ERAP1), showed evidence of an association with cHL in the genome-wide association study (OR = 1.21, 95% CI = 1.10 to 1.33, P = 1.5 × 10(-4)) and replication series (P = .03).ConclusionOverall, these results provide strong evidence that EBV status is an etiologically important classification of cHL and also suggest that some components of the pathological process are common to both EBV-positive and EBV-negative patients.