Kaposi sarcoma herpesvirus (KSHV) drives a devastating cancer that can leave painful lesions across the skin and internal organs. KSHV infection could in theory be prevented by a vaccine, stopping the cancer before it event starts. But an effective KSHV vaccine remains out of reach, largely because scientists don’t yet have a comprehensive understanding of how the virus infects host cells and how the immune system fights it.
A new study from the McGuire, Boonyaratanakornkit, Phipps, and Pancera Labs in the Vaccine and Infectious Disease Division sheds light on how protective antibodies disrupt a key viral protein to prevent infection, laying the groundwork for future vaccine design and cancer therapies.
KSHV can infect several types of human cells through a complicated process that relies on coordinated interactions between viral proteins and receptors on the surface of host cells. One critical pair of viral proteins in this process is glycoproteins H and L (gH/gL), which form a complex and trigger fusion of the viral and host cell membranes, making gH/gL a point of vulnerability for KSHV. Disrupting this step could prevent infection, but first researchers must identify which parts of gH/gL are most important for infection and most vulnerable to immune attack.
The immune systems of people infected with KSHV has already done this work. Infected individuals produce neutralizing antibodies (nAbs) that recognize viral proteins and block infection, acting as a frontline molecular defense and providing a natural blueprint to target the virus. The authors note, “Mapping the critical sites of vulnerability on the virus is important for future vaccine and therapeutic design.”
The team isolated a dozen gH/gL-specific antibodies from donors in Uganda and performed extensive biochemical and structural analyses. The researchers determined that seven of these antibodies could neutralize KSHV infection in epithelial cells, targeting slightly different regions of the gH/gL complex.
Two of these nAbs were particularly potent. Using electron microscopy, the team showed that they both bound gH/gL at the same site as a host-receptor EphA2, physically blocking the receptor and preventing viral entry. This finding underscores the importance of the EphA2 interaction in KSHV infection and highlights this region as a promising therapeutic target.
But not all neutralizing antibodies worked the same way. Several bound regions of gH/gL that are unrelated to EphA2 binding, suggesting alternative mechanisms of blocking viral entry that are not yet fully understood. These antibodies provide valuable clues, highlighting additional regions on the viral surface that could be susceptible to vaccines, and offer insights into how gH/gL may interact with other host receptors or viral proteins during infection.
To move beyond broad structural snapshots, the team turned to cryogenic electron microscopy, a technique that provides near-atomic-resolution 3D maps of antibody-virus complexes, pictured below. These detailed structures are essential for rational vaccine design, allowing scientists to engineer immunogens that focus the immune response on the most vulnerable targets.
Together, these findings define critical sites of vulnerability on KSHV and lay important groundwork for a KSHV vaccine. The authors note that the antibodies characterized in this study neutralized infection only in epithelial cells. Next, they plan to target other viral proteins that play key roles in B cell infection. By continuing to unravel how KSHV infects different cell types and which viral targets are most vulnerable, researchers are moving closer to a vaccine that could not only prevent infection, but also the cancers this virus causes.
The spotlighted research was funded by the National Cancer Institute, a Fred Hutch Vaccine and Infectious Disease Division Initiative Grant, and the National Institutes of Health.
Wan Y, Pernikoff S, Aldridge NT, Lang K, Dudley HM, Scharffenberger SC, Kher G, Phipps W, Pancera M, Boonyaratanakornkit J, McGuire AT. 2026. Monoclonal neutralizing antibodies elicited by infection with Kaposi sarcoma-associated herpesvirus reveal critical sites of vulnerability on gH/gL. PLOS Pathogens. DOI: 10.1371/journal.ppat.1013772
Science Spotlight writer Thamiya Vasanthakumar is a postdoctoral research fellow in the Campbell Lab at Fred Hutch. As a structural biologist, she uses cryogenic electron microscopy (cryoEM) to visualize the molecular structures of receptors found on the surface of immune cells.
For the Media