Hemophiliacs with symptomatic disease are multiply exposed to blood products including factor concentrates to correct the Internet clotting factor deficiencies. Prior to routine use of heat inactivation and screening of donor blood for specific viral pathogens, hemophilia patients were routinely exposed to, and infected with, viruses such as hepatitis B (HBV), hepatitis C (HCV) and human immunodeficiency virus (HIV). Cohort studies in hemophiliacs suggest several clinically and scientifically important findings that warrant further detailed investigation including; a) Liver disease progression may be altered in hemophiliacs infected with HCV with more rapid progression to liver failure and death; b) The source of infection from large pools of concentrate that were potentially infected by multiple discreet donors leads to a high risks of mixed infection represented by both genotype and quasi species heterogeneity; c) The HIV coinfected hemophiliacs may have different clinical outcomes and an altered immune response may facilitate our understanding of the underlying process of mutant virus selection, and the associated clinical outcomes. The overall goals of this proposal include the study and characterization of the genomic RNA of HCV in infected hemophilic patients with and without confection with HIV. In the retrospective Phase 1, we utilize the NCI Multi center Hemophiliac Cohort Study serum bank database to study the relationship between progression to decompensated liver disease and quasi species variability in the viral envelope hyper variable and core domain. Heteroduplex analysis will be used to rapidly screen samples from index patients and matched controls using samples longitudinally collected over a 10 year or longer period of time. Peptides will be produced from unique quasi species and these peptides will be evaluated for their function as CTL epitomes. Phase 2 involves the initiation and performance of a clinical intervention trial designed to determine variable kinetic response rates to PEG-interferon+ribavirin between hemophiliacs with HCV alone vs HCV/HIV coinfected subjects. Quasi species populations will be modified/cloned, sequencing will be performed to generate families of closely related core peptides that will be studied for their ability to bind and stimulate an immune response. Treatment nonresponders will be followed in a prospective cohort study for up to 3 additional years so that the evolution of the virus, and its associated immune response in this group can be evaluated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049508-02
Application #
6511362
Study Section
Special Emphasis Panel (ZAI1-YL-A (J1))
Program Officer
Matula, Margaret A
Project Start
2001-06-01
Project End
2005-05-31
Budget Start
2002-09-01
Budget End
2003-05-31
Support Year
2
Fiscal Year
2002
Total Cost
$689,116
Indirect Cost
Name
University of Cincinnati
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Sherman, Kenneth E; Rouster, Susan D; Stanford, Sandra et al. (2010) Hepatitis C virus (HCV) quasispecies complexity and selection in HCV/HIV-coinfected subjects treated with interferon-based regimens. J Infect Dis 201:712-9
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Graham, Camilla S; Wells, Annalee; Edwards, Erika M et al. (2007) Effect of exposure to injection drugs or alcohol on antigen-specific immune responses in HIV and hepatitis C virus coinfection. J Infect Dis 195:847-56
Shire, Norah J; Horn, Paul S; Rouster, Susan D et al. (2006) HCV kinetics, quasispecies, and clearance in treated HCV-infected and HCV/HIV-1-coinfected patients with hemophilia. Hepatology 44:1146-57
Mann, Elizabeth A; Stanford, Sandra; Sherman, Kenneth E (2006) Prevalence of mutations in hepatitis C virus core protein associated with alteration of NF-kappaB activation. Virus Res 121:51-7
Lienesch, Douglas; Morris, Robert; Metzger, Allan et al. (2005) Absence of cyclic citrullinated peptide antibody in nonarthritic patients with chronic hepatitis C infection. J Rheumatol 32:489-93
Qin, Hongxing; Shire, Norah J; Keenan, Erica D et al. (2005) HCV quasispecies evolution: association with progression to end-stage liver disease in hemophiliacs infected with HCV or HCV/HIV. Blood 105:533-41
Alatrakchi, Nadia; Graham, Camilla S; He, Qi et al. (2005) CD8+ cell responses to hepatitis C virus (HCV) in the liver of persons with HCV-HIV coinfection versus HCV monoinfection. J Infect Dis 191:702-9
Sherman, Kenneth E; Shire, Norah J; Cernohous, Paul et al. (2005) Liver injury and changes in hepatitis C Virus (HCV) RNA load associated with protease inhibitor-based antiretroviral therapy for treatment-naive HCV-HIV-coinfected patients: lopinavir-ritonavir versus nelfinavir. Clin Infect Dis 41:1186-95
Graham, Camilla S; Wells, Annalee; Liu, Tun et al. (2005) Antigen-specific immune responses and liver histology in HIV and hepatitis C coinfection. AIDS 19:767-73

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