Hepatitis B Infection: Immune Mechanisms Underlying Acute Infection

Embargo until
2020-12-01
Date
2018-08-27
Journal Title
Journal ISSN
Volume Title
Publisher
Johns Hopkins University
Abstract
Following acute hepatitis B virus (HBV) infection, some individuals develop protective antibodies and recover. Others develop chronic hepatitis B (CHB), a leading cause of liver-related morbidity and mortality. CHB is characterized by intermittent hepatic inflammation and HBV-specific immune impairment. Current antivirals neither target HBV-specific immunity, nor eliminate the stable viral DNA within hepatocytes; thus, treatment is often lifelong. Improving our understanding of the immune mechanisms necessary to elicit recovery and overcome the immunotolerant hepatic microenvironment may facilitate development of a cure. This thesis begins with a study of CHB prevalence in a Tibetan community living in Bylakuppe, India. Of 2,769 individuals tested, 247(8.9%) had CHB, and 613 (22.2%) had serological evidence of prior recovery from HBV infection, demonstrating that CHB remains highly endemic in some populations (Chapter 2). In Chapters 3 and 4, immune mechanisms in acute HBV are examined to identify responses associated with recovery. To better understand the finding that the non-functional chemokine receptor CCR5 enhanced recovery from acute HBV in humans, Ccr5+/+ and Ccr5-/- mice were intravenously infected with an adenovirus containing the overlapping HBV-1.3 construct (AdHBV); intrahepatic immune dynamics were assayed by flow cytometry and ELISA. Following AdHBV infection, Ccr5-/- mice had enhanced infiltrating CD11b+ NK cells at Day 3 and pro-inflammatory CD11b+Ly6chi monocytes at Day 14. Previous studies have demonstrated both NK cells and CD11b+Ly6chi monocytes can improve HBV-specific T cell responses and facilitate recovery. In Chapter 4, cytokines were assayed in individuals with incident HBV infection from the Multicenter AIDS Cohort Study (MACS). Of 110 HIV-uninfected individuals with incident HBV, 10 (9%) developed CHB. Elevated MIP1, MIP1, IP-10, IL-10, and IL-18 were observed during acute infection in HBsAg+ HIV-uninfected individuals with detectable antibodies to HBcAg (anti-HBc), but no differences were observed by HBV outcome. Interestingly, in HBsAg+ HIV-uninfected individuals tested prior to detection of anti-HBc, CCL17 was elevated in those that developed CHB. CCR4, a cognate receptor for CCL17, drives hepatic regulatory T cells recruitment, suggesting a mechanistic explanation for development of CHB. Together, these findings point to two potential targets for treatment of CHB (CCR4 and CCR5) that require future attention.
Description
Keywords
Hepatitis B, HBV, CCR5, CCL17, NK Cells, Ly6chi monocytes, CXCL10, IP10, CXCR3
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