Exploring Mechanisms of Hepatitis C Virus-Associated Xerostomia - PROJECT SUMMARY/ABSTRACT Chronic hepatitis C virus (HCV) infection remains one of the major causes of chronic liver disease, cirrhosis and liver cancer, and is a major public health issue worldwide, with an estimated prevalence of 170 million people globally. With no prophylactic HCV vaccine available, HCV remains difficult to eradicate. Newer generations of Direct-Acting Antivirals (DAA) are effective in eliminating the virus in up to 95% of the patients, however, this treatment remains out of reach for many individuals. Multiple HCV extrahepatic manifestations (EHM) have been reported in patients with chronic HCV infection including chronic lymphocytic sialadenitis, and sicca syndrome indistinguishable from Sjögren’s syndrome (SS). Yet, the mechanisms of the xerostomia and salivary gland (SG) hypofunction remain controversial. Thus, understanding the clinical aspects of HCV-associated xerostomia is of interest to better assess and manage this symptom. The objectives of this project are to determine the pathophysiologic changes in the minor salivary glands (MSG) and changes in saliva composition associated with chronic HCV infection and correlate these changes with clinical features of SG hypofunction (mentored phase) and to mechanistically describe the HCV-associated xerostomia (independent phase). To achieve this goal, Dr. José Maldonado-Ortiz will work with a mentoring team including Dr. John Chiorini (primary mentor), Dr. Blake Warner (co-mentor), Dr. Raj Gopalakrishnan (collaborator), Dr. Valeria De Giorgi (collaborator), and Nobel laureate Dr. Harvey Alter (collaborator). In Aim 1, the pathophysiologic changes in the MSG of patients with chronic HCV infection will be determined and correlated to xerostomia and clinical features of salivary dysfunction in patients with and without complaints of xerostomia. In Aim 2, the effects of HCV DAA therapy in salivary physiology will be determined and correlated to clinical features of xerostomia. To understand the pathophysiology of chronic HCV-associated SG dysfunction (Aim 1), and the effects of DAA therapy in SG function, MSG biopsies will be collected and used to provide histopathological evidence of SG damage/changes and research tissues to perform RNAseq and scRNAseq, in addition to sialometry, sialochemistry, and ultrasonography of the major SG. Dry mouth and oral health related quality of life instruments will be completed. In Aim 3, the mechanisms of HCV induced salivary gland dysfunction will be determined in vivo. To this end, an adeno-associated virus (AAV) vector expressing the antigenic HCV envelope proteins E1 and E2 will be transferred into the submandibular SG of mice to 1) better understand the HCV/host immune cell interactions and 2) tissue changes that may result in SG dysfunction. In combination, these studies will reveal new information about viral infections and the triggering or initiation of SG diseases such as SS. HCV infection offers a unique opportunity to study viral induced SG dysfunction and can provide mechanistic data on the role of viruses in driving inflammation, dysfunction, and damage in the SG.
