The overall objective of this Mentored Patient-Oriented Research Career Development Award is to integrate the candidate's background in patient-oriented research with new training in molecular virology to understand the molecular basis of interferon response in the treatment of chronic hepatitis C (HCV). Hepatitis C infection is the leading cause of clinical liver disease in the U.S. Interferon treatment responses vary greatly in HCV infection, and are particularly poor in HIV-infected and African-American patients. In this grant, the candidate will examine the effect of interferon on viral kinetics of HCV during therapy in patients representing a range of clinical scenarios. We hypothesize that sequence variation in the NS5A region and the diversity of HCV quasispecies influence the 1st phase slope (decline) induced by interferon therapy. To test this hypothesis, we will closely examine the viral kinetics at early time points in HCV-infected patients with and without HIV among an equal number of African Americans and Caucasians to identify those with rapid vs. slower initial interferon responses. Next, using molecular cloning and sequencing techniques, we will determine the complexity and diversity of the HCV genome prior to initiation of interferon therapy and at these same early time points after initial interferon dosing. Sequencing the entire NS5A region of each clone will be used to correlate specific mutations with 1st phase slope and with genomic complexity and diversity using bioinformatics techniques. Characterization of early viral kinetics and NS5A molecular changes during interferon therapy in populations that have different response rates to interferon therapy may provide novel insights into mechanisms of interferon action with the goal of improving treatment responses. Combining in-depth training in molecular virology with the candidate's strong background in patient-oriented research, HIV medicine, and hepatology will prepare her to become an independent investigator in the area of HIV/HCV co-infection. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AI065630-04
Application #
7470087
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Koshy, Rajen
Project Start
2005-08-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
4
Fiscal Year
2008
Total Cost
$124,200
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Jain, M K; Adams-Huet, B; Terekhova, D et al. (2015) Acute and chronic immune biomarker changes during interferon/ribavirin treatment in HIV/HCV co-infected patients. J Viral Hepat 22:25-36
Dubin, Perry H; Yuan, Hejun; Devine, Robert K et al. (2014) Micro-RNA-122 levels in acute liver failure and chronic hepatitis C. J Med Virol 86:1507-14
Jain, Mamta K; Pasipanodya, Jotam G; Alder, Lara et al. (2013) Pegylated interferon fractal pharmacokinetics: individualized dosing for hepatitis C virus infection. Antimicrob Agents Chemother 57:1115-20
Yuan, Hejun; Adams-Huet, Beverley; Petersen, Tianna et al. (2012) A single nucleotide polymorphism in IL28B affects viral evolution of hepatitis C quasispecies after pegylated interferon and ribavirin therapy. J Med Virol 84:1913-9
Dao, Doan Y; Balko, Jody; Attar, Nahid et al. (2011) Hepatitis B virus genotype G: prevalence and impact in patients co-infected with human immunodeficiency virus. J Med Virol 83:1551-8
Jain, Mamta K; Yuan, He-Jun; Adams-Huet, Beverley et al. (2009) Pegylated interferon and ribavirin promote early evolution of nonstructural 5A protein in individuals with hepatitis C who demonstrate a response to treatment. J Infect Dis 200:866-76
Jain, M K; Aragaki, C; Fischbach, L et al. (2007) Hepatitis C is associated with type 2 diabetes mellitus in HIV-infected persons without traditional risk factors. HIV Med 8:491-7
Jain, Mamta K; Opio, Christopher K; Osuagwu, Chukwuma C et al. (2007) Do HIV care providers appropriately manage hepatitis B in coinfected patients treated with antiretroviral therapy? Clin Infect Dis 44:996-1000