Role of HLA-G in Viral Infections.

Simon Jasinski-Bergner,Ofer Mandelboim,Barbara Seliger,Dominik Schmiedel

doi:10.3389/fimmu.2022.826074

Abstract

The human leukocyte antigen (HLA)-G is a non-classical HLA class I molecule, which has distinct features to classical HLA-A, -B, -C antigens, such as a low polymorphism, different splice variants, highly restricted, tightly regulated expression and immune modulatory properties. HLA-G expression in tumor cells and virus-infected cells, as well as the release of soluble HLA-G leads to escape from host immune surveillance. Increased knowledge of the link between HLA-G expression, viral infection and disease progression is urgently required, which highlights the possible use of HLA-G as novel diagnostic and prognostic biomarker for viral infections, but also as therapeutic target. Therefore, this review aims to summarize the expression, regulation, function and impact of HLA-G in the context of different viral infections including virus-associated cancers. The characterization of HLA-G-driven immune escape mechanisms involved in the interactions between host cells and viruses might result in the design of novel immunotherapeutic strategies targeting HLA-G and/or its interaction with its receptors on immune effector cells.

Highlights

Accumulating evidence exists that immune suppressive mechanisms play a critical role in promoting viral infections by either suppressing the capacity of infected host cells to overcome viral infection or by preventing the elimination of virus-transformed cells by immune effector cells
The interaction of these receptors with human leukocyte antigen (HLA)-G leads to the inhibition of the cytolytic function of natural killer (NK) cells and CD8+ cytotoxic T lymphocytes (CTLs), macrophage-mediated cytotoxicity, allo-proliferative response of CD4+ T cells and of the maturation as well as function of dendritic cells (DCs)
Disease outcome was not clearly linked to HLAG variants despite a meta-analysis listed the HLA-G 3’untranslated region (UTR) single nucleotide polymorphism (SNP) rs9381042 as a candidate variant that was slightly overrepresented in a UK cohort of critically ill patients due to COVID-19 infection compared to the general population (Table 1) [49]

Summary

INTRODUCTION

Accumulating evidence exists that immune suppressive mechanisms play a critical role in promoting viral infections by either suppressing the capacity of infected host cells to overcome viral infection or by preventing the elimination of virus-transformed cells by immune effector cells. The interaction of these receptors with HLA-G leads to the inhibition of the cytolytic function of natural killer (NK) cells and CD8+ cytotoxic T lymphocytes (CTLs), macrophage-mediated cytotoxicity, allo-proliferative response of CD4+ T cells and of the maturation as well as function of dendritic cells (DCs). The HLA-G-derived nonamer VMAPRTLFL presented on HLA-E molecules caused an enhanced NK cell-mediated lysis in an in vitro experiment of transfected 721.221 cells naturally lacking HLA class Ia/b molecules thereby representing valuable targets for NK cells It needs to be addressed in much more detail whether this effect plays a role in vivo, especially in the context of sHLA-G molecules within the TME of solid tumors inhibiting immune effector cells even prior to tumor infiltration. The region downstream of the 14 bp ins/del polymorphic site has been

Regulatory impact

Findings

CONCLUSIONS