Liver disease caused by infection with Hepatitis C Virus (HCV) is a leading cause of death in HIV-infected persons, and is of particular importance among injection drug users (IDUs). Several cofactors worsen HCV progression, including HIV, age, and enhanced HCV replication. Since HIV and aging impact on each other and on HCV replication, demonstrating their independent contributions to liver disease progression has been challenging up till now. This proposal is conceived to investigate the role and mechanism(s) underlying liver disease progression in HCV-infected IDUs using innovative and complementary tools in the clinic and lab. In the first aim, the effect of HIV on aging in the liver will be studed using structured longitudinal measurements of liver stiffness in a cohort of HIV-infected and - uninfected persons, and especially on the effect of suppressive HAART on fibrosis progression rates. Nested mechanistic studies are planned to understand how HIV contributes to the aging liver.
The second aim, focused on HCV replication, leverages advances in tissue imaging and specimen collection to study single hepatocytes from archived HCV-infected human biopsies. Absent a representative model of human HCV infection, molecular signatures of HCV- infected hepatocytes will be compared within the same person to those of uninfected hepatocytes, identifying potential therapeutic targets for HCV control.
The third aim i s centered on understanding HCV replication in the context of the transition of HCV infection from treatment-responsive during acute infection to treatment-resistant during chronic infection, extending the observation that the IL28B gene locus strongly predicts treatment responsiveness in chronic infection. Persons with favorable and unfavorable IL28B genotypes will be followed during acute infection and early chronic infection with structured measurements of immune activation and tolerance in peripheral blood mononuclear cells and liver tissue to target mechanisms underlying treatment resistance. The proposed studies will define key pathways of liver disease progression in HCV-infected IDUs. The overall long-term public health impact of a successful proposal is to a) attenuate the progression of liver disease in IDUs and b) to identify relevant molecular targets for HCV control.

Public Health Relevance

Hepatitis C infection is rampant in injecting drug users, and is the leading cause of liver transplantation in the United States. Hepatitis C is made worse by HIV, advancing age, and in certain people with a genetic polymorphism that render them resistant to treatment. The aim of this proposal is to understand how the progression of Hepatitis C infection is worsened by age, HIV, and immune-related genes with the hopes of identifying pathways that can be reversed.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Khalsa, Jagjitsingh H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Mave, Vidya; Erlandson, Kristine M; Gupte, Nikhil et al. (2016) Inflammation and Change in Body Weight With Antiretroviral Therapy Initiation in a Multinational Cohort of HIV-Infected Adults. J Infect Dis 214:65-72
Balagopal, Ashwin; Gupte, Nikhil; Shivakoti, Rupak et al. (2016) Continued Elevation of Interleukin-18 and Interferon-γ After Initiation of Antiretroviral Therapy and Clinical Failure in a Diverse Multicountry Human Immunodeficiency Virus Cohort. Open Forum Infect Dis 3:ofw118
Balagopal, Ashwin; Thio, Chloe L (2015) Editorial Commentary: Another Call to Cure Hepatitis B. Clin Infect Dis 61:1307-9
El-Diwany, Ramy; Wasilewski, Lisa N; Witwer, Kenneth W et al. (2015) Acute Hepatitis C Virus Infection Induces Consistent Changes in Circulating MicroRNAs That Are Associated with Nonlytic Hepatocyte Release. J Virol 89:9454-64
Kurbanov, Fuat; Kim, Yonghak; Latanich, Rachel et al. (2015) IFNL3 genotype is associated with differential induction of IFNL3 in primary human hepatocytes. Antivir Ther 20:805-14
Balagopal, Ashwin; Thomas, David L (2015) Editorial Commentary: Who is ""Special"" Now? Clin Infect Dis 61:826-8
Tenforde, Mark W; Gupte, Nikhil; Dowdy, David W et al. (2015) C-reactive protein (CRP), interferon gamma-inducible protein 10 (IP-10), and lipopolysaccharide (LPS) are associated with risk of tuberculosis after initiation of antiretroviral therapy in resource-limited settings. PLoS One 10:e0117424
Balagopal, Ashwin; Barin, Burc; Quinn, Jeffrey et al. (2015) Immunologic Predictors of Liver Transplantation Outcomes in HIV-HCV Co-Infected Persons. PLoS One 10:e0135882
Balagopal, Ashwin; Asmuth, David M; Yang, Wei-Teng et al. (2015) Pre-cART Elevation of CRP and CD4+ T-Cell Immune Activation Associated With HIV Clinical Progression in a Multinational Case-Cohort Study. J Acquir Immune Defic Syndr 70:163-71
Graw, Frederik; Balagopal, Ashwin; Kandathil, Abraham J et al. (2014) Inferring viral dynamics in chronically HCV infected patients from the spatial distribution of infected hepatocytes. PLoS Comput Biol 10:e1003934

Showing the most recent 10 out of 69 publications