Hepatitis C is the leading indication for liver transplantation. Patients transplanted for hepatitis C virus (HCV) disease universally develop re-infection of the allograft. The resultant hepatitis has an accelerated course. With the continued shortage of donor organs, it is crucial to develop strategies to promote long-term graft survival. We hypothesize that in the immune suppressed transplant recipient, HCV genetic features play a dominant role in disease progression. The principal goal of this proposal is to determine the impact of HCV genomic variability on the outcome of recurrent hepatitis C in liver allograft recipients. We propose to examine clinical and viral data under three different scenarios to test the hypothesis that an association exists between levels of genetic diversity in HCV and the severity of recurrent hepatitis following transplantation. We will assess the levels of viral diversity prior to and following liver transplantation in a group of individuals from whom samples and clinical outcomes are available. Further, to gain a more clear understanding of changes in viral evolutionary dynamics associated with liver transplantation, we will track viral evolutionary changes at several time points leading to and immediately following transplantation in a small number of individuals. This study will test the presence of a relationship between viral diversity and transplantation outcome, as defined by the severity of hepatitis on allograft biopsy one year following transplantation. It will also reveal changes in viral evolutionary dynamics over a window encompassing liver transplantation. Much of the genetic analyses will be undertaken by Heteroduplex Mobility Assay (HMA). Selected samples that show interesting profiles in HMA will be sequenced and examined by phylogenetic analyses. Clinical evaluation will include recipient and donor demographics, details of immunosuppression and episodes of rejection, and graft and patient survival. Patients will be categorized to have mild or severe disease. The two groups will be compared for differences in clinical and laboratory variables including the HMA score. A statistical model will be created to predict severe disease. If validated such a model will greatly enhance our ability to optimize transplant outcomes. Completing the specific aim of this proposal may also provide valuable information about key aspects of host-viral interactions and the influence of such interactions on disease course.
| Habib, Shahid; Berk, Brian; Chang, Chung-Chou H et al. (2006) MELD and prediction of post-liver transplantation survival. Liver Transpl 12:440-7 |
| Kesturu, Girish S; Colleton, Bonnie A; Liu, Yi et al. (2006) Minimization of genetic distances by the consensus, ancestral, and center-of-tree (COT) sequences for HIV-1 variants within an infected individual and the design of reagents to test immune reactivity. Virology 348:437-48 |
