HLA Class I and II alleles, heterozygosity and HLA-KIR interactions are associated with rates of genital HSV shedding and lesions

Abstract

Variation at HLA and KIR loci is associated with the severity of viral infections. To assess associations of genital HSV-2 infection with human HLA and KIR genetic loci, we measured the frequencies of genital HSV DNA detection and of genital lesions in HSV-2 seropositive persons. We followed 267 HSV-2 seropositive persons who collected daily genital swabs and recorded lesions for ≥30 days. All persons were laboratory- documented as HIV-seronegative, and all were Caucasian by self-report. HSV detection rate and lesion frequency were compared by genotype using Poisson regression. Overall, HSV was detected on 19.1% of days and lesions on 11.6% of days. The presence of HLA-A*01 was directly associated with HSV detection frequency while the presence of HLA-C*12 was inversely associated with HSV detection frequency. The presence of HLA-A*01 was directly associated with lesion rate, while HLA-A*26, -C*01 and -DQB1*0106 were associated with decreased lesions. We observed an interaction between the absence of both 2DS4del and HLA-Bw4 and higher lesion rate. Heterozygosity of HLA was also associated with reduced lesion frequency. Immune control of genital HSV infection relies on multiple interacting immunogenetic elements, including epistatic interactions between HLA and KIR.

Molecular epidemiology of enteroviruses in young children at increased risk of type 1 diabetes

“…In the present study, the children who were heterozygous for HLA-DQ2 and -DQ8 had fewer EV infections than the children who were homozygous for these haplotypes. This is in line with other studies suggesting that homo- and heterozygosity in the HLA alleles may modulate the course of a viral infection [ 44 , 45 ]. It is possible that heterozygous individuals present a wider range of EV peptides to T-helper cells than homozygous individuals.…”

Herpes simplex virus‐2 dynamics as a probe to measure the extremely rapid and spatially localized tissue‐resident T‐cell response

“…It is a signature feature of HSV‐2 infection that instances of relative immunologic success and failure occur commonly within the same person over time. For nearly all human pathogens, including HSV‐2, a major focus of clinical and immunologic research is to develop a better understanding of what drives differences in disease severity or manifestations between persons by identifying viral and host‐related correlates of protection from infection or disease . Indeed, HSV‐2 infection is characterized by “low” and “high” shedders, the latter of whom is most likely to experience frequent and bothersome disease manifestations .…”

“…For nearly all human pathogens, including HSV-2, a major focus of clinical and immunologic research is to develop a better understanding of what drives differences in disease severity or manifestations between persons by identifying viral and host-related correlates of protection from infection or disease. 64 Indeed, HSV-2 infection is characterized by "low" and "high" shedders, the latter of whom is most likely to experience frequent and bothersome disease manifestations. 23,63 In the case of HSV-2, similarly important comparisons must also be made within a singleinfected person.…”

Genome-wide association study (GWAS) of human host factors influencing viral severity of herpes simplex virus type 2 (HSV-2)

“…As a complex trait, infection severity is potentially influenced by a combination of viral ( 18 ), host ( 19 – 21 ), and environmental factors. The importance of host genetic variation in herpes pathogenesis has previously been demonstrated for certain rare phenotypes, such as herpes simplex virus type 1 encephalitis (HSE) ( 22 , 23 ).…”

“…It is well-established that neuron-intrinsic deficiencies in toll-like receptor 3 (TLR3) pathway genes result in severe childhood HSE after primary HSV-1 infection ( 22 , 24 ). For HSV-2, candidate gene studies have implicated viral control and immune genes, including TLRs, in both susceptibility ( 25 – 28 ) and severity ( 19 – 21 ) during the chronic phase. Although these studies have detected variants potentially associated with herpes pathogenesis, they were limited to a small number of common allelic variants in candidate genes and none of these candidate gene associations have been replicated by other, independent studies.…”