Viruses are masters of stealth, often lurking silently in our bodies. For the Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8 (HHV-8), the human mouth serves as an unexpected hub for infectious viral particles capable of silently spreading the virus. Best known as the viral culprit behind Kaposi Sarcoma (KS) – a common cancer in sub-Saharan Africa marked by vascular lesions primarily affecting the skin and mucous membranes – KSHV belongs to the gammaherpesvirus family. Unlike alpha and betaherpesvirus, gammaherpesviruses are uniquely associated with tumor formation, particularly in individuals with weakened immune systems, such as those undergoing cancer treatment or infected with human immunodeficiency virus (HIV).
KSHV is most infectious when it exits its dormant latent phase to enter the lytic phase, during which the virus replicates and newly formed virus particles are released from the host cell via a process called shedding. Similar to how humans and animals shed excess hair, a replicating virus sheds their viral progeny, and in the case of KSHV, this frequently occurs in our saliva. For reasons we do not yet understand, shedding varies dramatically between individuals, raising critical questions: Do individuals with KS shed more KSHV particles? Is KSHV shedding altered in patients living with HIV? What is the standard duration for an episode of KSHV shedding, and are there differences in the amount of KSHV produced in these episodes?
These are the questions that drive Elizabeth Krantz, a statistical research associate in Dr. Joshua Schiffer’s lab at Fred Hutch’s Vaccine and Infectious Disease Division. In a recent study published in Open Forum Infectious Diseases, Krantz and the Schiffer lab investigated how factors such as KS status, defined by the presence of cancerous lesions, and HIV coinfection coincide with oral shedding. To explore these mysteries, the team conducted a longitudinal study in Uganda, collecting saliva samples from a diverse cohort and measuring the amount of KSHV particles present. As KSHV is frequently associated with HIV co-infection, the study included participants with both KSHV and HIV, those with either KSHV or HIV, and uninfected controls. By examining the frequency, quantity, and duration of viral shedding over time, the researchers aimed to determine how factors like KS status, HIV coinfection, and immune function shape KSHV’s shedding dynamics.
The study revealed a rollercoaster of shedding kinetics. While some people shed the virus continuously, others did so sporadically – or even not at all! This heterogeneity seemed influenced by coinfections, such as HIV, and the presence of KS itself. Think of it as viral activity on a dimmer switch – brightening and dimming based on environmental cues and host factors. However, these factors were not sufficient to account for all the variability observed. “It is particularly surprising that low, medium, and high shedders are seen in people with and without Kaposi sarcoma, and with and without HIV,” notes Schiffer. Krantz adds, “Understanding what drives these distinct shedding patterns beyond KS and HIV status could be instrumental in guiding future vaccine development.” This study highlights KSHV’s shedding as a viral mystery still waiting to be fully untangled – one that may hold the key to stopping this pathogen’s silent spread.
Dr. Schiffer is a member of the Translational Data Science Integrated Research Center (TDS IRC).
Krantz E. M., Mutyaba I., Nankoma J., Okuku F., Casper C., Orem J., Swan D. A., Phipps W., Schiffer J. T. Highly Heterogeneous Kaposi Sarcoma–Associated Herpesvirus Oral Shedding Kinetics Among People With and Without Kaposi Sarcoma and Human Immunodeficiency Virus Coinfection. (2024). Open Forum Infectious Diseases, Volume 11, Issue 10. https://doi.org/10.1093/ofid/ofae548.
Science Spotlight writer Jenny Waters is a postdoctoral research fellow in the Hsieh lab at Fred Hutch. She studies how mRNA translation coordinates bladder cancer transformation and metastasis by post-transcriptionally regulating expression of oncogenic proteins. Outside of the lab, Jenny enjoys spending time with her dogs, convincing her husband to join her on trail runs, and pretending every steep hill is just a "gentle incline."
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