Host Genetic Factors in Susceptibility to Herpes Simplex Type 1 Virus Infection: Contribution of Polymorphic Genes at the Interface of Innate and Adaptive Immunity

Abstract

HSV-1 establishes life-long latency that can result in clinical relapses or in asymptomatic virus shedding. Although virtually all adults have been exposed to HSV-1, the clinical course varies remarkably. Genetic host variability could be related to this clinical diversity. In this study, we analyzed the contribution of gene families in chromosomes 1, 6, 12, and 19, which encode key regulators of the innate and adaptive immunity, in a cohort of 302 individuals. Class I and class II alleles of the HLA system, the copy-number variation of NK cell receptor genes (KIR and NKG2C), the combinations of killer cell Ig-like receptor and their HLA ligands, and CD16A and CD32A allotypes of variable affinity for IgG subclasses were all studied. Although no major susceptibility locus for HSV-1 was identified, our results show that the risk of suffering clinical HSV-1 infection is modified by MHC class I allotypes (B*18, C*15, and the group of alleles encoding A19), the high-affinity receptor/ligand pair KIR2DL2/HLA-C1, and the CD16A-158V/F dimorphism. Conversely, HLA class II and CD32A polymorphisms and NKG2C deletion did not seem to influence the clinical course of herpetic infection. Collectively, these findings support an important role in host defense against herpetic infection for several polymorphic genes implicated in adaptive immunity and in surveillance of its subversion. They confirm the crucial role of cytotoxic cells (CTL and NK) and the contribution of genetic diversity to the clinical course of HSV-1 infection.

NK Cell and Ig Interplay in Defense against Herpes Simplex Virus Type 1: Epistatic Interaction of CD16A and IgG1 Allotypes of Variable Affinities Modulates Antibody-Dependent Cellular Cytotoxicity and Susceptibility to Clinical Reactivation

“…Indeed, previous studies related the development of autoimmune processes with functional polymorphisms in both FCGR3A and FCGR2C (14,21), and with FCGR3B deletion (22,23) that determines ectopic CD32B expression on NK cells. Paradoxically, the possible influence of the FcgR polymorphism on the defense against viral infection has not been explored sufficiently; in this regard, we showed previously that homozygosis for the higheraffinity allele CD16A-158V is associated with an asymptomatic course of HSV-1 infection, whereas the CD32A-131H/R dimorphism is not (2).…”

“…Although exposure to HSV-1 is virtually universal in adults, the clinical course of the infection varies greatly and depends, in part, on host genetic factors, including polymorphisms at the interface of innate and adaptive immunity, like those of KIR and their HLA ligands and the IgG receptor CD16A (1)(2)(3). Viral replication is controlled by both branches of the immune response, of which key components are human NK cells.…”

Protection From Varicella Zoster in Solid Organ Transplant Recipients Carrying Killer Cell Immunoglobulin-Like Receptor B Haplotypes

“…No effect of KIR haplotype was seen regarding replication of HSV and BKPyV, which stands somewhat in contradiction to previous studies partly done in healthy donors. 9,10 However, this may reflect the different role for NK cells in patients with compromised adaptive immunity and the sites of reactivation. In summary, we find that telomeric B-haplotype KIR genes are associated with protection from VZV reactivation after SOT.…”

“…Laurent Schmied, 1 Grzegorz Terszowski, 1 Asensio Gonzalez, 1 Karin Schmitter, 1 Hans H. Hirsch, 2,3 Christian Garzoni, 4,5 Christian van Delden, 6 Katia Boggian, 7 Nicolas J. Mueller, 8 Christoph Berger, 9 Jean Villard, 10 Oriol Manuel, 11 Pascal Meylan, 11 Christoph Hess, 12 Martin Stern, 1 …”

“…Recipient B haplotype and high numbers of activating KIR genes have been linked with protection from cytomegalovirus replication after solid organ transplantation (SOT) in a number of studies. 6,7 More recently, several studies have suggested that KIR genes may also associate with the risk for other viral infections, such as hepatitis C, 8 herpes simplex, 9 BK polyomavirus (BKPyV), 10 and influenza. 11 For Epstein-Barr virus (EBV) and varicella zoster virus (VZV), 2 further members of the human herpes virus family, evidence for involvement of NK cells in disease control recently emerged, but no possible correlation with KIR genotype has been investigated yet.…”