Project Information

Hepatitis C Virus Classification

  • Group: Group IV ((+)ssRNA, no DNA stage)
  • Family: Flaviviridae
  • Genus: Hepacivirus
  • Species: Hepatitis C virus

Significance

Hepatitis C is an emerging infection and a burgeoning worldwide public health problem, with 170 million infected and an estimated 20 million deaths in the coming decades. HCV is a major cause of liver cirrhosis, liver failure and hepatocellular carcinoma, infecting an estimated 170 million individuals worldwide [1]. Furthermore, HCV has emerged as an important cause of morbidity and mortality in HIV-infected subjects [2,3]. While drug treatments are available, clear limitations in access and efficacy require concerted efforts to develop effective prophylactic and therapeutic vaccines.

Host Immune Escape Project

The inherent sequence diversity of Hepatitis C Virus (HCV) represents an enormous challenge facing development of an effective HCV vaccine. Recent studies in HIV suggest that evolution of highly variable pathogens is not random, but influenced by evasion of host immune pressures [4,5]. Understanding the forces shaping HIV sequence diversity is helping to predict the evolution of HIV and to identify immune responses capable of exerting these selective pressures, issues central to the design of an effective vaccine. Recent data in HCV suggests very similar forces are at work to shape HCV sequence diversity [6], but little work has been done to date.

The Broad Insitute's HCV genome project aims to sequence the entire HCV genome of over 500 North American (genotype 1a & 1b) strains. To maximize the power of these studies and leverage existing resources, samples are derived from patients in whom full HLA class I typing (A, B, C loci) is available. Sequence data from this project will be used to identify HLA-associated polymorphisms in HCV at the population level and the role of immune pressures in shaping both regional and global HCV diversity. In addition these data will allow a comparison of the population structure of 1a and 1b subtypes found in Asian versus Western populations.

This project is supported by the NIAID funded Broad Institute Microbial Sequencing Center.

Principle Collaborators: Todd Allen and Thomas Kuntzen.

Rare Genotype & Subtype Characterization Project

HCV is a highly variable virus. Currently 6 genotypes are distinguished, and each genotype is further subdivided into a varying number of subtypes. These subtypes are often defined only on the basis of short sequence fragments, which are clearly distinct from other sequences in that region. As a consequence, a myriad of poorly defined subtypes now exist, and new ones are added monthly. This is leading to a confusing and inconsistent classification of HCV strains. This project aims to increase the genomic resources available for rare genotypes & subtypes of HCV. 35 rare HCV genomes will be sequenced as part of this project.

This project is supported by the NIAID funded Broad Institute Microbial Sequencing Center.

Principle Collaborators: Todd Allen, Thomas Kuntzen, and Carla Kuiken

References

  1. Lauer, G.M. & Walker, B.D. Hepatitis C virus infection. N Engl J Med 345, 41-52 (2001).
  2. Graham, C.S. et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis 33, 562-9 (2001).
  3. Martinez-Sierra, C. et al. Progression of chronic hepatitis C to liver fibrosis and cirrhosis in patients coinfected with hepatitis C virus and human immunodeficiency virus. Clin Infect Dis 36, 491-8 (2003).
  4. Moore, C.B. et al. Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level. Science 296, 1439-43. (2002).
  5. Leslie, A.J. et al. HIV evolution: CTL escape mutation and reversion after transmission. Nat Med 10, 282-9 (2004).
  6. Timm, J. et al. Human leukocyte antigen-associated sequence polymorphisms in HCV reveal reproducible immune responses and constraints on viral evolution. Hepatology 46, 339-349 (2004).