Extracellular vesicles secreted by HBV-infected cells modulate HBV persistence in hydrodynamic HBV transfection mouse model

Abstract

<jats:p>Hepatitis B, a viral infection that affects the liver, is thought to affect over 257 million people worldwide, and long-term infection can lead to life-threatening issues such as cirrhosis or liver cancer. Chronic hepatitis B develops by the interaction between Hepatitis B virus (HBV) and host immune response. However, questions of how HBV-infected cells thwart immune system defenses remain unanswered. Extracellular vesicles (EVs) are used for cellular communication, carrying cargoes such as RNAs, proteins and lipids and delivering them intracellularly after being endocytosed by target cells. HBV-infected liver cells secrete several types of EVs into body fluids such as complete and incomplete virions, and exosomes. We previously demonstrated that monocytes that incorporated EVs moved to immunoregulatory phenotypes via upregulation of PD-L1, an immunocheckpoint molecule, and downregulation of CD69, a leukocyte activation molecule. In this study, we transfected mice with HBV using hydrodynamic injection and studied the effects of EVs secreted by HBV-infected liver cells. EVs secreted from cells with HBV replication strongly suppressed the immune response, inhibiting the eradication of HBV-replicating cells in the mice transfected with HBV. EVs were systemically incorporated in multiple organs, including liver, bone marrow (BM) and intestine. Intriguingly, the BM cells which incorporated EVs acquired intestinal tropism and the dendritic cell populations in the intestine increased. These findings suggest that the EVs secreted by HBV-infected liver cells exert immunosuppressive functions, and that an association between the liver, bone marrow and intestinal tract exists through EVs secreted from HBV-infected cells.</jats:p>

Extracellular Vesicles as a Means of Viral Immune Evasion, CNS Invasion, and Glia-Induced Neurodegeneration

“…While some studies have shown that EVs from virus-infected cells can enhance the host’s immune response against the virus (Walker et al, 2009 ; Cypryk et al, 2017 ), most research suggests that EVs from virus-infected cells manipulate the immune response in favor of increased viral infection. For example, treatment of mice with EVs from cells infected with hepatitis B virus reduced the number of infiltrating mononuclear cells, suggesting EVs from infected cells can suppress the innate immune response (Kakizaki et al, 2020 ). Additionally, nasopharyngeal carcinoma cells, which are positive for Epstein-Barr virus (EBV), were found to release EVs containing galectin-9 and latent membrane protein-1, both of which have been associated with inhibition of T-cell proliferation (Keryer-Bibens et al, 2006 ).…”

Proteomic and phospholipidomic characterization of extracellular vesicles inducing tumor microenvironment in Epstein‐Barr virus‐associated lymphomas

“…Western blot analysis was performed as described previously 23 . Fractionated EV samples were subjected to electrophoresis under nonreducing conditions.…”

“…Western blot analysis was performed as described previously. 23 Fractionated EV samples were subjected to electrophoresis under nonreducing conditions. Membranes were incubated with anti-CD63 primary antibody (Santa Cruz Biotechnology, Santa Cruz, CA, USA) for 1 hour at room temperature.…”

SARS-CoV-2: A Master of Immune Evasion

“…Exosomes generated by virus-infected cells can negatively influence the immune response, and, according to most researchers, they affect it to benefit the increased viral proliferation [ 192 ]. Exosomes from hepatitis B virus-infected cells, for example, lowered the number of invading mononuclear cells in mice, implying that exosomes from infected cells can dampen the antibody immune response [ 210 ]. Viruses can also elude the immune system by altering the composition of exosomes.…”