Virus-Associate Exosomes in Inducing MDSC Differentiation and Suppression on Host Immunity for Persistent Infection and Vaccine Nonresponsiveness
Abstract
Approximately 200 million (3%) people worldwide and 4 million (1.8%) U.S. citizens are infected with hepatitis C virus (HCV). The Department of Veterans Affairs (VA) Clinical Case Registry (CCR) records an HCV infection rate in Veterans of ~10%, which is 5 times higher than the 1.8% infection rate in the general population. Thus, Veterans comprise the majority of HCV-infected population in the United States. Since chronic hepatitis C is associated with an increased risk of developing liver cirrhosis and hepatocellular carcinoma -- a leading cause for liver transplantation -- the annual deaths and cost from HCV-induced liver diseases will triple over the next 10 to 20 years. Per Centers for Disease Control and Prevention (CDC) reports, the number of HCV-related deaths is reaching an all-time high, surpassing 60 other nationally reportable infectious diseases combined and making hepatitis C the number one infectious disease that kills people in the United States. While direct acting antiviral (DAA) therapies have significantly improved HCV treatment, these therapeutic cocktails are facing new concerns, such as viral mutation, relapse, and reinfection following therapy. Conversely, the success of developing DAA therapies provides an excellent opportunity to study the immune regulation by HCV before and after antiviral treatment in humans. Currently, the lack of an HCV vaccine is a major hurdle to control this global infection. Moreover, chronically HCV-infected patients respond poorly to hepatitis B virus (HBV) vaccines (only ~50% seroconversion after immunizations). Thus, it is critical to understand the mechanisms underlying HCV-induced immune dysregulation leading to viral persistence and vaccine non-responsiveness. Clearance of viral infection and effective vaccine response depend on robust T and B cell immune responses. Importantly, we and others have recently discovered an expansion of myeloid-derived suppressor cells (MDSC), a heterogeneous population of immature myeloid cells with immunosuppressive activities, in the peripheral blood of individuals with chronic viral (HCV, HIV) infections, where they can inhibit host immune responses. We have also identified HCV-RNA-containing exosomes (cell-derived, membrane-enclosed extracellular microvesicles that serve as natural carrier of signaling molecules) in the plasma of HCV-infected subjects and in the supernatant of HCV-infected cell lines. The overall goal of this proposal is to uncover the mechanisms by which these virus-associated exosomes regulate the generation and function of MDSCs during infection. The ultimate aim is to understand role of exosomes in suppressing host immunity, resulting in vaccine failure and chronic infection in humans. To this end, we will use HCV-infected individuals with defined HBV vaccine responses as a model, since HCV is highly efficient (~80%) at establishing persistent infection via suppression of host immunity, and HBV vaccine responses have been deemed as an in vivo readout of the host immune status. This study is highly relevant to the Peer Reviewed Medical Research Program (PRMRP) Topic Areas - Hepatitis B and C – focusing on “vaccination for those unable to mount immunity to hepatitis B virus” and “strategy to developing a vaccine against hepatitis C.” The proposed research project also addresses a PRMRP Area of Encouragement on “Vaccine Development for Infectious Diseases in evaluation of humoral and cellular immune responses after vaccination compared to natural infection.” In summary, this application will characterize the nature and capacity of exosomes derived from HCV plasma with different disease stages to induce MDSCs and immune dysfunctions and determine their roles in HBV vaccine failure during chronic HCV infection. A better understanding of these novel mechanisms may provide new targets for immunotherapy and vaccination strategies. Thus, this study is highly relevant to military personnel, Veterans, a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810327
Entities
People
- Zhi Yao
Organizations
- United States Army