Understanding the role of HLA genes to cytomegalovirus (CMV) infection: A new breakthrough

Have you ever wondered why some people get sick from a virus while others remain healthy? Scientists have been exploring this question for years, and a recent study has made exciting progress in understanding how our genes influence our response to a common virus called cytomegalovirus (CMV).

CMV is a widespread virus that infects most people at some point in their lives. For healthy individuals, it often causes no symptoms. However, in newborns, transplant recipients, or people with weakened immune systems, CMV can lead to serious complications such as hearing loss, cognitive impairment, or organ damage. Because of its global impact, developing effective vaccines and treatments remains a high priority for clinicians and researchers.

The role of HLA genes: what did the study find?

The study, led by Juliano Boquett* et al and published in The American Journal of Human Genetics (April 2025), examined the relationship between human leukocyte antigen (HLA) genes and susceptibility to CMV infection. HLA genes play a crucial role in the immune system by helping the body recognize and respond to viruses.

To uncover how these genetic differences affect CMV infection, Boquett and his team analyzed data from more than half a million immunocompetent, healthy volunteers across two large donor registries (NMDP and DKMS). They combined high-resolution HLA genotyping with information about CMV antibody status, age, sex, and socioeconomic background. Using advanced computational models, they also explored how subtle structural changes in HLA molecules influence the way viral peptides are presented to immune cells, offering a mechanistic explanation for the genetic associations observed.

Through this large-scale approach, the team identified two HLA class II variants, HLA-DRB1*01:03, and HLA-DRB1*04:03, that were consistently associated with CMV serostatus (whether someone has been exposed to CMV). The one variant, HLA-DRB1*01:03 was linked to protection, while HLA-DRB1*04:03 was associated with increased susceptibility. Interestingly, these alleles are quite rare, suggesting that even small genetic differences can significantly affect the immune response to CMV.

Why is this important?

Understanding how these genetic variations shape our response to CMV offers key insights for both research and clinical practice:

• Vaccine development: Knowing which genetic factors contribute to protection or risk can guide the design of vaccines that are effective across diverse genetic backgrounds.

• Targeted treatments: Insights into HLA-related immune responses could help tailor prevention or treatment strategies for individuals who are more vulnerable to CMV infection.

• Transplant compatibility: Since CMV reactivation is a major risk in transplantation, these findings could help improve donor-recipient matching and post-transplant care.

What comes next?

This study represents the most comprehensive investigation to date of HLA variation and CMV infection in healthy individuals. The next steps will be to explore how these genetic differences influence immune responses over time and to use these insights to guide vaccine and immunotherapy design.

Interested to find out more about this study?

Watch Dr. Juliano Boquett’s webinar, hosted by GenDx, where he discusses his findings: click here

To access the full article, click here