Examining the dynamics of Epstein-Barr virus shedding in the tonsils and the impact of HIV-1 coinfection on daily saliva viral loads

Epstein-Barr virus (EBV) is transmitted by saliva and is a major cause of cancer, particularly in people living with HIV/AIDS. Here, we describe the frequency and quantity of EBV detection in the saliva of Ugandan adults with and without HIV-1 infection and use these data to develop a novel mathematical model of EBV infection in the tonsils. Eligible cohort participants were not taking antiviral medications, and those with HIV-1 infection had a CD4 count >200 cells/mm3. Over a 4-week period, participants provided daily oral swabs that we analysed for the presence and quantity of EBV. Compared with HIV-1 uninfected participants, HIV-1 coinfected participants had an increased risk of EBV detection in their saliva (IRR = 1.27, 95% CI = 1.10–1.47) and higher viral loads in positive samples. We used these data to develop a stochastic, mechanistic mathematical model that describes the dynamics of EBV, infected cells, and immune response within the tonsillar epithelium to analyse potential factors that may cause EBV infection to be more severe in HIV-1 coinfected participants. The model, fit using Approximate Bayesian Computation, showed high fidelity to daily oral shedding data and matched key summary statistics. When evaluating how model parameters differed among participants with and without HIV-1 coinfection, results suggest HIV-1 coinfected individuals have higher rates of B cell reactivation, which can seed new infection in the tonsils and lower rates of an EBV-specific immune response. Subsequently, both these traits may explain higher and more frequent EBV detection in the saliva of HIV-1 coinfected individuals.
Author summary Epstein-Barr virus (EBV) is a ubiquitous infection worldwide associated with the development of several kinds of cancer, including B cell lymphoma and nasopharyngeal carcinoma. Rates of EBV replication and disease are higher in individuals who are coinfected with HIV-1. HIV-1 infection is associated with increased B cell activation as well as immunodeficiency resulting from loss of T cells; however, whether these factors contribute to higher rates of EBV replication during coinfection, and by how much, has remained unknown. We analysed oral EBV shedding data from a cohort of Ugandan adults taken at multiple time points and found that participants coinfected with HIV-1 maintained higher quantities of EBV in their saliva. To better understand this finding, we developed a mathematical model to describe the dynamics of EBV infection within the tonsils. By rigorously matching our model to our participant data, we determined that both high rates of infected B cell activation and worse cellular immune control of EBV may cause higher EBV loads in saliva during HIV-1 coinfection. These results help explain the impact of HIV-1 on EBV and suggest potential therapeutic targets to prevent EBV-related malignancy in people who are coinfected with HIV-1.