Human Leukocyte Antigens (HLA) are cell surface molecules, central in coordinating innate and adaptive immune responses, that are targets of strong diversifying natural selection by pathogens. Of these pathogens, human herpesviruses have a uniquely ancient relationship with our species, where coevolution likely has reciprocating impact on HLA and viral genomic diversity. Consistent with this notion, genetic variation at multiple HLA loci is strongly associated with modulating immunity to herpesvirus infection. Here, we synthesize published genetic associations of HLA with herpesvirus infection and disease, both from case/control and genome-wide association studies. We analyze genetic associations across the eight human herpesviruses and identify HLA alleles that are associated with diverse herpesvirus-related phenotypes. We find that whereas most HLA genetic associations are virus- or disease-specific, HLA-A*01 and HLA-A*02 allotypes may be more generally associated with immune susceptibility and control, respectively, across multiple herpesviruses. Connecting genetic association data with functional corroboration, we discuss mechanisms by which diverse HLA and cognate receptor allotypes direct variable immune responses during herpesvirus infection and pathogenesis. Together, this review examines the complexity of HLA-herpesvirus interactions driven by differential T cell and Natural Killer cell immune responses.

人类白细胞抗原 (HLA) 是细胞表面分子，在协调先天性和适应性免疫反应中发挥核心作用，是病原体强烈多样化自然选择的目标。在这些病原体中，人类疱疹病毒与我们物种有着独特的古老关系，共同进化可能对 HLA 和病毒基因组多样性产生相互影响。与这一观点一致，多个HLA位点的遗传变异与调节对疱疹病毒感染的免疫力密切相关。在这里，我们综合了已发表的 HLA 与疱疹病毒感染和疾病的遗传关联，这些关联来自病例/对照和全基因组关联研究。我们分析了八种人类疱疹病毒的遗传关联，并鉴定了与不同疱疹病毒相关表型相关的 HLA 等位基因。我们发现，虽然大多数 HLA 遗传关联是病毒或疾病特异性的，但 HLA-A*01 和 HLA-A*02 同种异型可能更普遍地分别与多种疱疹病毒的免疫易感性和控制相关。将遗传关联数据与功能确证联系起来，我们讨论了不同的 HLA 和同源受体同种异型在疱疹病毒感染和发病机制期间指导可变免疫反应的机制。这篇综述共同探讨了由差异性 T 细胞和自然杀伤细胞免疫反应驱动的 HLA-疱疹病毒相互作用的复杂性。