This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chronic hepatitis C virus (HCV) infection is a major threat to the public health. Current therapies have limited efficacy, but the search for more effective treatments is hampered by the lack of available animal models of HCV infection. The chimpanzee (Pan troglodytes) is the only animal species permissive for infection with this virus. We will address this deficiency by developing a small nonhuman primate model of hepatitis C involving the closely related virus GBV-B. GBV-B replicates to high titers, is hepatotropic, and causes liver disease in susceptible tamarins (Saquinus sp.). Since tamarins are more readily available than chimpanzees for such studies, GBV-B infection of these animals represents a potentially useful surrogate for studies of hepatitis C. However, although GBV-B among all animal viruses has the closest phylogenetic relationship to HCV, its proteins still share only ~25% identity at the amino acid level. Moreover, unlike HCV, GBV-B does not appear capable of establishing persistent infection in these animals. These features of GBV-B limit its usefulness. To overcome these limitations, we will construct chimeric genome-length GBV-B cDNA clones in which specific functional domains of HCV are inserted in lieu of homologous GBV-B sequence. Our hypothesis is that the close phylogenetic relationship between GBV-B and HCV will allow the rescue of viable chimeric viruses from these clones, and that these viruses will represent uniquely valuable resources to the research community since they will allow the in vivo evaluation of HCV antivirals.
Under Aim 1, we will construct a full-length, infectious cDNA copy of the GBV-B genome.
In Aim 2, we will construct infectious chimeric cDNAs between HCV and GBV-B.
In Aim 3, we will construct chimeras in which the structural proteins of GBV-B and HCV are placed within the genetic background of the alternate virus.
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