Hepatitis B Infection: Immune Mechanisms Underlying Acute Infection
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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.