The purpose of this retrospective pilot study is to identify adaptive mutations that are selected in nonstructural coding regions of the hepatitis C virus (HCV) genome. The dominant virus population that was present in women co-infected with Human Immunodeficiency virus (HIV) and HCV, when clinical signs of progressive liver disease were apparent, will be analyzed. The long-term goal is to understand the viral genomic characteristics of HCV that result in enhanced viral replication, and lead, in conjunction with host immunity and environmental factors, to liver damage. The central hypothesis is that efficient replication of specific HCV variants with enhanced growth properties contributes to liver damage. It is postulated that the enhancement of viral replication is due to the selection of adaptive mutations in the nonstructural coding regions of the genome. This viral population can then become dominant over time in a hepatic environment in which control of viral replication has been weakened by HIV-induced immunosuppression, alcohol and substance abuse. To test this hypothesis we will sequence the NS3/NS4A and NS5B nonstructural coding regions of the HCV genome in virus from HIV-HCV co-infected women with and without clinical signs of progressive liver disease. The rationale for the proposed research is that once specific mutations are identified as markers of advanced disease, a prognostic assay can be developed to identify patients at higher risk of progression. The study population is 100 HlV-HCV co-infected women, with the additional risk factors of alcohol and substance abuse, enrolled in the Women's Interagency HIV Study (WIHS) at SUNY Downstate in Brooklyn, NY. The experienced investigators collaborating on this proposal represent the cross-disciplinary fields of molecular virology, HIV-HCV primary care and clinical research, and biostatistics. The WIHS cohort at SUNY Downstate has been selected, not only because of the availability of robust demographic and clinical information and stored plasma samples collected since 1994, but also because of the potential for expansion to include the entire WIHS cohort of >2,000 women. HIV-HCV co-infected individuals have been specifically chosen because of the mounting evidence that HIV infection exacerbates HCV disease. Liver failure has become a leading cause of death in the HIV-HCV co-infected population, emphasizing the urgent public health need for earlier treatment intervention.
