Increased oral Epstein-Barr virus shedding with HIV-1 co-infection is due to a combination of B cell activation and impaired cellular immune control

Abstract

Epstein-Barr virus (EBV) infection is transmitted by saliva and is a major cause of cancer in people living with HIV/AIDS as well as in the general population. To better understand the determinants of oral EBV shedding we evaluated the frequency and quantity of detectable EBV in the saliva in a prospective cohort study of 85 adults in Uganda, half of whom were co-infected with HIV-1. Participants were not receiving antiviral medications, and those with HIV-1 co-infection had a CD4+ T cell count >200 cells/mm 3 . Daily, self-collected oral swabs were collected over a 4-week period. Compared with HIV-1 uninfected participants, co-infected participants had an increased frequency of oral EBV shedding (IRR=1.27, 95% CI=1.10-1.47). To explain why EBV oral shedding is greater in HIV-1 co-infected participants, we developed a stochastic, mechanistic mathematical model that describes the dynamics of EBV, infected cells, and antiviral cellular immune responses within the tonsillar epithelium, and examined March 19, 2019 1/30 parameter-specific differences between individuals of different HIV-1 infection statuses. We fit the model to our observational data using Approximate Bayesian Computation. After fitting, model simulations showed high fidelity to daily oral shedding time-courses and matched key summary statistics. Examination of the model revealed that higher EBV loads in saliva are driven by B cell activation causing EBV lytic replication in the tonsils, in combination with a less effective EBV-specific cellular immune response. Thus, both these factors contribute to higher and more frequent EBV shedding in HIV-1 co-infected individuals compared to HIV-1 uninfected individuals. These conclusions were further validated by modelling daily oral EBV shedding in a 26-participant North American cohort. Our results provide insights into the determinants of EBV shedding and implicate B cell activation to be a potential therapeutic target to reduce EBV replication in HIV-1 co-infected individuals at high risk for EBV-related malignancies. Author summaryEpstein-Barr virus (EBV) is a ubiquitous infection worldwide. Infection with EBV is 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 also infected with HIV-1. HIV-1 infection is associated with increased B cell activation, which is known to induce EBV reactivation, as well as immunodeficiency resulting from loss of T cells. However, whether these factors contribute to higher rates of EBV replication during co-infection, and by how much, was unknown. We analysed oral EBV shedding data in a cohort of adults from Uganda that were chronically infected with EBV. We found that participants that were HIV-1 infected were much more likely to have detectable quantities of EBV in their saliva. Also, when detected, the quantity of EBV present in the saliva was usually higher in HIV-1 infected participants. To better understand these findings, we developed...

Gastrointestinal helminths increase Bordetella bronchiseptica shedding and host variation in supershedding

“…These could include, but are not limited to, immune-mediated control of bacteria turnover in the mucosa or stochastic events during bacteria release, such as random mucus discharge, and also variation in host behavior. Our finding is consistent with other systems where fast, intermittent shedding was reported both from single ( Hadinoto et al, 2009 ; Schiffer et al, 2009 ; Rolin et al, 2014 ; Spencer et al, 2015 ; Slater et al, 2016 ) and co-infected hosts ( Byrne et al, 2019 ; Kao et al, 2007 ). A compelling study by Hadinoto et al, 2009 on Epstein-Barr virus shedding in healthy carriers showed that the virus was rapidly and continuously shed in the saliva but the process of virus production and control was regulated by multiple factors, including the immune response.…”

“…These could include, but are not limited to, immune-mediated control of bacteria turnover at the epithelium/ mucosa level or stochastic events during bacteria release, such as random mucus discharge, and also variation in host behavior. Overall, our findings are consistent with other systems where fast and intermittent shedding has been reported both from single [6,19,[42][43][44] and co-infected hosts [12,45]. Our model framework and variables selected, prevented us from capturing the intrinsic and local mechanism responsible for these rapid changes, including the processes generating supershedding events, and more work at the epithelial level is need to explain these patterns and the relative contribution of the lower and upper respiratory tract.…”

“…While studies on the immunological response to multi-species infections has provided insight to the interactions between the host and its pathogens, there remains a need to identify how these processes relate to onward transmission, specifically the patterns of bacterial shedding. Dynamical mathematical models are particularly useful in disentangling these complexities as they can generate mechanistic-driven hypotheses that can be examined in relation to empirical data ( Smith et al, 2013 ; Byrne et al, 2019 ). In the current study, we applied this general approach to investigate the dynamics of shedding of the respiratory bacterium Bordetella bronchiseptica in rabbits experimentally co-infected with one or both of the gastrointestinal helminths Trichostrongylus retortaeformis and Graphidium strigosum .…”

Herpesviral Latency—Common Themes

“…Further research has shown that activation of Toll-like receptors 6 and 7 (TLR6 and TLR7) by other viruses can trigger KSHV reactivation [180]. Similarly, previous studies suggest that HIV-1, HPV, HHV-6, Plasmodium falciparum, Leptospirosis, and Group A Streptococci stimulate EBV reactivation [183][184][185][186][187][188]. In the case of EBV, it was also highlighted that the lytic cycle can be induced by Treponema pallidum through TLR2 and B-cell receptor (BCR) activation [189].…”