Science Spotlight

Genetic variation influences HSV-2 shedding

Koelle lab (Vaccine and Infectious Disease Division and Public Health Sciences Division)

Herpes simplex virus 2 (HSV-2) infects an estimated 417 million people worldwide between the ages of 15-49. HSV-2 is a sexually transmitted virus that causes genital herpes and persists life long. Severity and clinical symptoms differ between people and patient response is most likely regulated by host determinants, which are poorly understood. It is known that T cell deficient patients experience increased HSV-2 infection suggesting a starting place for understanding this relationship. Human leukocyte antigen (HLA) is a gene complex that encodes the major histocompatibility complex (MHC) proteins. These cell surface proteins help regulate the human immune system, presenting peptides or antigens from foreign pathogens to T cells thus triggering an immune response. Since T cells are so important for control of HSV-2 infection, HLA type is hypothesized to correlate with infection outcome. In addition to T cells, natural killer (NK) cells also contribute to HSV-2 control, this is done through the killer- cell immunoglobulin-like receptor (KIR). Like HLA there are many variances of KIR in the human population.

In a study by Drs. Magaret, Koelle, and Ward (Vaccine and Infectious Disease Division, Fred Hutch and University of Washington) published in Genes and immunity the authors investigated the link between host genetics and the range of HSV-2 severity. To this end, the authors studied a cohort of 267 HSV-2 infected persons who provided lesion records and daily swabs and who were genotyped for HLA class as well as KIR loci. With the combined shedding results, lesion history, and genetic information for this large cohort, the study yielded results with increased statistical power over smaller, previous studies. Due to sample sizes and differences in genetics due to race, the authors focused on HSV-2 infected healthy Caucasians with a median age of 41.

Image of the regression tree showing shedding and HLA type.
Regression tree assessing association between shedding rate and HLA type. The HSV shedding rate is represented under each category.

After collecting viral shedding, lesion history, and genetic data from the participants, the authors looked for correlations between the HLA or KIR alleles and shedding and/or lesion. Viral shedding, measured by PCR, revealed a correlation between the number of unique HLA alleles, showing that having five to six alleles is associated with decreased shedding. Taking a closer look at allele usage, a few alleles emerged as positive correlates of shedding, HLA-A*01, -B*08 and –C*07. Conversely, HLA-A*26, -B38, and –C*12 were associated with decreased shedding. In a multivariate model considered shedding rates in the context of age, gender, HSV-1 co-infection, and time since acquisition HLA-A*01 and HLA-C*12 were significantly correlated with viral shedding increase and decrease, respectively. Taking a closer look at viral lesion data, the authors found a similar relationship regarding number of unique alleles, with more alleles present leading to lower lesion frequency. They also discovered that homozygosity at either HLA-B or HLA-DRB1 loci correlated with increased lesion frequency. After adjusting for patient variability HLA-A*01, -C*12 and –DQB1*06 was associated with change in lesion rate with –A*01 increasing and both –C*12 and DQB1*06 decreasing lesion frequency. After screening the HLA correlates the authors considered the effects of KIR loci on HSV-2 infection. When looking at KIR and HLA interactions, they found that having both HLA C class I and KIR-3DS1 receptor was associated with higher shedding and lesion rate. However, after taking into account the multiple comparison by HLA, only the absence of both KIR-2DS4del and HLA-Bw4 was associated with increased lesion rate. This absence was greatly influenced by two participants and therefore needs to be further studied.

In conclusion, the study showed that in a large Caucasian cohort that HLA-A*01 and –C*12 positively and negatively regulate viral shedding, respectively. In addition, –A*01 was also associated with increases lesion frequency. Lowered lesion rate was associated with HLA-A*26, -C*01, and –DQB1*0106. It also appears that an increased number of unique HLA alleles may aid in control of disease. As more and more studies like this are published it is becoming clear that scientists and doctors need to understand host genetics in regards to viral infections, especially in the context of vaccine design and disease outcome. This paper lays the groundwork for elucidating host factors of HSV-2 disease. Dr. Koelle commented, “The article shows that an individual's genetic background at the most hypervariable human genetic locus, the HLA locus, is correlated with about a 1.5-fold change in the severity of the chronic phase of HSV-2 infection.  Typical of many complex traits, individual genetic loci tend to have small, but statistically significant, contributions. The with the HLA A and B alleles imply that differences in CD8 T cells mediate the effects that we detected.”

Magaret A, Dong L, John M, Mallal SA, James I, Warren T, Gaudieri S, Koelle DM, Wald A. 2016. HLA Class I and II alleles, heterozygosity and HLA-KIR interactions are associated with rates of genital HSV shedding and lesions. Genes Immun.

Funding provided by the National Institutes of Health.