Hepatitis B virus (HBV) is a hepatotropic, enveloped, partially double-stranded DMA virus that causes acute and chronic hepatitis with progression to cirrhosis and hepatocellular carcinoma (HCC). Despite an effective vaccine, over 350 million people throughout the world are chronically infected with HBV and may be at risk for progressive liver disease without optimal antiviral therapy. While HBV clearance is associated with robust and broad virus-specific IFN(+ type 1 effector T cell responses, viremia persists with impaired virus-specific effector T cells that cannot clear viremia but may nonetheless contribute to disease pathogenesis. Based on published literature and our own preliminary data implicating immune regulatory (FoxP3+ Tregs, IL-10) and costimulatory (PD-1) pathways in chronic viral infections including HBV, we hypothesize that the outcome of HBV infection and therapy is defined by the balance between antiviral effector and regulatory T-cell responses that are further shaped by innate signals. We also propose that targeted inhibition of negative immune regulatory pathways may reverse the antiviral effector dysfunction and unmask the underlying effector capacity for prolonged virus control. To this end, we will examine the following 3 specific aims to determine if: 1) HBV persists with distinct effector and regulatory T-cell responses that can predict clinical and therapeutic outcomes;2) Virus suppression during HBV therapy will enhance antiviral effector T-cell function and reduce inhibitory immune regulatory factors;3) Modulation in adaptive immune responses with therapeutic HBV suppression is defined by innate immune response. The proposed studies will provide insights to the mechanisms of immune dysfunction in HBV persistence, define potential early immunological markers to prognosticate therapeutic outcome and to define future immune-based strategies to enhance long term therapeutic outcome.
|Di Bisceglie, A M; Lombardero, M; Teckman, J et al. (2017) Determination of hepatitis B phenotype using biochemical and serological markers. J Viral Hepat 24:320-329|
|Lok, A S; Ganova-Raeva, L; Cloonan, Y et al. (2017) Prevalence of hepatitis B antiviral drug resistance variants in North American patients with chronic hepatitis B not receiving antiviral treatment. J Viral Hepat 24:1032-1042|
|Evon, Donna M; Wahed, Abdus S; Johnson, Geoffrey et al. (2016) Fatigue in Patients with Chronic Hepatitis B Living in North America: Results from the Hepatitis B Research Network (HBRN). Dig Dis Sci 61:1186-96|
|Park, Jang-June; Wong, David K; Wahed, Abdus S et al. (2016) Hepatitis B Virus--Specific and Global T-Cell Dysfunction in Chronic Hepatitis B. Gastroenterology 150:684-695.e5|
|Ghany, Marc G; Perrillo, Robert; Li, Ruosha et al. (2015) Characteristics of adults in the hepatitis B research network in North America reflect their country of origin and hepatitis B virus genotype. Clin Gastroenterol Hepatol 13:183-92|
|Khalili, Mandana; Lombardero, Manuel; Chung, Raymond T et al. (2015) Diabetes and prediabetes in patients with hepatitis B residing in North America. Hepatology 62:1364-74|
|Chang, Kyong-Mi (2010) Hepatitis B immunology for clinicians. Clin Liver Dis 14:409-24|