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

Byrne, C. M.; Johnson, C.; Orem, J.; Okuku, F.; Huang, M.-L.; Selke, S.; Wald, A.; Corey, L.; Schiffer, J. T.; Casper, C.; Coombs, D.; Gantt, S.

doi:10.1101/587063

bioRxiv · 10.1101/587063

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

Byrne, C. M.·Johnson, C.·Orem, J.·Okuku, F.·Huang, M.-L.·Selke, S.·Wald, A.·Corey, L.·Schiffer, J. T.·Casper, C.·Coombs, D.·Gantt, S.

View original source ↗Export metadata ↓

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/mm3. 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 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.\n\nAuthor 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 a mathematical model to describe the dynamics of EBV, EBV-infected cells, and the cellular immune response within the tonsils. By rigorously matching our model to our participant data, we determined that high EBV loads in saliva are caused by high rates of infected B cell activation, as well as worse cellular immune control of EBV infection. These results provide an explanation of the impact of HIV-1 on EBV infection. Further, they suggest that strategies that suppress B cell activation may prevent EBV-related malignancy in people who are also infected with HIV-1.

Explore related subjects

pathology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Byrne, C. M., Johnson, C., Orem, J., Okuku, F., Huang, M.-L., Selke, S., Wald, A., Corey, L., Schiffer, J. T., Casper, C., Coombs, D., Gantt, S.. 2019-03-24. 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. https://doi.org/10.1101/587063

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

NAE1-Dependent Protein Neddylation Preserves Endothelial Identity and Vascular Integrity

Background: Endothelial dysfunction is a central driver of cardiovascular and inflammatory diseases, yet the post-translational mechanisms that preserve endothelial homeostasis remain incompletely understood. Protein neddylation, the covalent conjugation of a ubiquitin-like modifier, regulates diverse cellular processes, yet its physiological role in the vascular endothelium remains unknown. This study investigated whether protein neddylation is required to preserve endothelial identity and vascular homeostasis. Methods: We generated tamoxifen-inducible endothelial-specific Nae1 knockout mice to inhibit neddylation and combined bulk RNA sequencing, single-cell and single-nucleus transcriptomics, quantitative proteomics, biochemical analyses, and gain- and loss-of-function approaches to define the role of endothelial neddylation in vascular homeostasis and inflammatory injury. Results: Endothelial-specific Nae1 deletion caused rapid mortality associated with vascular leakage, platelet accumulation, inflammation, and multi-organ injury. Multi-omics analyses demonstrated profound loss of endothelial identity, characterized by suppression of core endothelial programs and activation of inflammatory, procoagulant, and pyroptotic pathways. Single-cell analyses revealed progressive endothelial dysfunction culminating in depletion of the endothelial population and remodeling of the vascular niche. Mechanistically, endothelial neddylation deficiency activated gasdermin D (GSDMD)- and gasdermin E (GSDME)-dependent pyroptosis, whereas dual inhibition of GSDMD and GSDME markedly attenuated inflammatory transcriptomic remodeling, vascular injury, hepatocyte death, immune cell infiltration, and platelet accumulation. Translational analyses demonstrated reduced endothelial neddylation in experimental endotoxemia and decreased expression of neddylation pathway components in human atherosclerosis and COVID-19 datasets. Conversely, restoration of endothelial neddylation partially reversed inflammatory endothelial transcriptomic reprogramming in vivo. Conclusions: NAE1-dependent protein neddylation is an essential regulator of endothelial identity and vascular integrity. Loss of endothelial neddylation promotes gasdermin-dependent pyroptosis and thrombo-inflammatory vascular injury, whereas restoration of the neddylation pathway mitigates inflammatory endothelial dysfunction. These findings identify endothelial neddylation as a fundamental mechanism maintaining vascular homeostasis and a potential therapeutic target for cardiovascular and inflammatory diseases.

pathology↗

bioRxiv2019

Loss of MLKL Decreases Necrotic Core but Increases Macrophage Lipid Accumulation In Atherosclerosis

ObjectivesDuring the advancement of atherosclerosis, the cellularity of the plaque is governed by the influx of monocyte-derived macrophages and their turnover via apoptotic and non-apoptotic forms of cell death. Previous reports have demonstrated that programmed necrosis, or necroptosis, of macrophages within the plaque contribute to necrotic core formation. Knockdown or inhibition of the necrosome components RIPK1 and RIPK3 slow the progression of atherosclerosis, and activation of the terminal step of necroptosis, MLKL, has been demonstrated in advanced human atherosclerotic plaques. However, whether MLKL directly contributes to lesion development and necrotic core formation has not been investigated.\n\nApproaches and ResultsMLKL expression was knocked down in atherogenic Apoe- knockout mice via subcutaneous administration of antisense oligonucleotides (ASO). During advanced atherogenesis, Mlkl knockdown potently reduced cell death in the plaque, with a significant reduction in the necrotic core. However, total lesion area in the aortic sinus remained unchanged. Furthermore, treatment with the MLKL ASO unexpectedly reduced circulating cholesterol levels compared to control ASO, while staining for lipids within the plaque was significantly increased. Peritoneal macrophages transfected with the MLKL ASO showed increased lipid loading upon incubation with modified cholesterol-rich lipoproteins. In lipid-loaded macrophages, MLKL co-localized with Rab7, a marker of the late endosome.\n\nConclusionsThese studies confirm the requirement for MLKL as the executioner of necroptosis, and as such a significant contributor to the necrotic core during atherogenesis. We also identified a previously unknown role for MLKL in interacting with endosomal trafficking components to regulate lipid uptake in macrophages during atherogenesis.

pathology↗

bioRxiv2019

Desmin is a modifier of dystrophic muscle features in Mdx mice

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disease, caused by dystrophin deficiency. Desmin is like dystrophin associated to costameric structures bridging sarcomeres to extracellular matrix that are involved in force transmission and skeletal muscle integrity. In the present study, we wanted to gain further insight into the roles of desmin which expression is increased in the muscle from the mouse Mdx DMD model. We show that a deletion of the desmin gene (Des) in Mdx mice (DKO, Mdx:desmin-/-) induces a marked worsening of the weakness (reduced maximal force production) as compared to Mdx mice. Fragility (higher susceptibility to contraction-induced injury) was also aggravated and fatigue resistance was reduced in DKO mice. Moreover, in contrast to Mdx mice, the DKO mice did not undergo a muscle hypertrophy because of smaller and less numerous fibers, with reduced percentage of centronucleated fibres. Interestingly, Desmin cDNA transfer with adeno-associated virus in 1-month-old DKO mice and newborn Mdx mice improved muscle weakness. Overall, desmin plays important and beneficial roles on muscle performance, fragility and remodelling in dystrophic Mdx mice.

pathology↗