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.
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.
| El-Diwany, Ramy; Soliman, Mary; Sugawara, Sho et al. (2018) CMPK2 and BCL-G are associated with type 1 interferon-induced HIV restriction in humans. Sci Adv 4:eaat0843 |
| Shivakoti, Rupak; Ewald, Erin R; Gupte, Nikhil et al. (2018) Effect of baseline micronutrient and inflammation status on CD4 recovery post-cART initiation in the multinational PEARLS trial. Clin Nutr : |
| McCarthy, Elisa K; Vakos, Amanda; Cottagiri, Merylin et al. (2018) Identification of a Shared Cytochrome p4502E1 Epitope Found in Anesthetic Drug-Induced and Viral Hepatitis. mSphere 3: |
| Sugawara, Sho; Thomas, David L; Balagopal, Ashwin (2018) HIV-1 Infection and Type 1 Interferon: Navigating Through Uncertain Waters. AIDS Res Hum Retroviruses : |
| Quinn, Jeffrey; Astemborski, Jacquie; Mehta, Shruti H et al. (2017) HIV/HCV Co-infection, Liver Disease Progression, and Age-Related IGF-1 Decline. Pathog Immun 2:50-59 |
| Kandathil, Abraham Joseph; Sugawara, Sho; Balagopal, Ashwin (2017) Erratum to: Are T cells the only HIV-1 reservoir? Retrovirology 14:11 |
| El-Diwany, Ramy; Breitwieser, Florian P; Soliman, Mary et al. (2017) Intracellular HIV-1 RNA and CD4+ T-cell activation in patients starting antiretrovirals. AIDS 31:1405-1414 |
| Soliman, Mary; Srikrishna, Geetha; Balagopal, Ashwin (2017) Mechanisms of HIV-1 Control. Curr HIV/AIDS Rep 14:101-109 |
| Kandathil, Abraham J; Breitwieser, Florian P; Sachithanandham, Jaiprasath et al. (2017) Presence of Human Hepegivirus-1 in a Cohort of People Who Inject Drugs. Ann Intern Med 167:1-7 |
| Kandathil, Abraham Joseph; Sugawara, Sho; Balagopal, Ashwin (2016) Are T cells the only HIV-1 reservoir? Retrovirology 13:86 |
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