Among six genotypes, the genotype 6 represents the oldest, most diverse and genetically most complex viruses. This genotype currently has 22 subtypes, including 6r-6v we designated. We have sequenced the first complete genomes of 16 subtypes and 2 equivalents. We have also discovered 16 variants that may represent 14 new subtypes and 36 variants that show great genetic differences. The overall goal of this application is to define the genetic variation and virology properties of HCV by conducting detailed analyses on a full panel of genotype 6 complete sequences that will be determined from these variants. Based on the sequences, we will assemble full length HCV genomes and use for developing new HCV cell culture models. The rationale is that clarifying these HCV sequences will enable many bioinformatics analyses that have applications linking to basic research to patient care.
The Specific Aims are to: (1) determine the complete genomes of 71 genotype 6 variants showing substantial genetic variations;(2) determine the epidemic dynamics of HCV that is represented by the oldest genotype 6 variants;and (3) develop HCV genotype 6 cell culture models using unique HCV genomes that are defined in (1). It is hypothesized that HCV genotype 6 represents a """"""""living viral fossil"""""""" that will best reflect the past history of the virus and that, being the most complex among all HCV genotypes, the genotype 6 variants may have higher divergent properties that may make them more suitable for cell cultures. To accomplish these aims, we will employ an improved DNA walking strategy that can sequence a complete HCV genome from only 100 ?l of serum. We will use the BEAST software that combines various coalescent methods. Novel strategies will be recruited to obtain the full length HCV genomes from the most infectious virus particles. In wild type or in chimeras with the JFH1 isolate, these genomes will be used to develop new HCV cell culture models that will have many applications. The successful completion of these studies will contribute the missing and fundamental knowledge to the epidemic dynamics of HCV, bioinformatic definition of its genetic variations, and the novel approaches in developing new HCV cell culture models. These models with the sequence will be vital for basic HCV research and for patient care and public health.

Public Health Relevance

successful completion of these studies will contribute new viral sequences and cell culture models to understand the HCV genetic variation, epidemiology behavior, and virology mechanisms. This information and the derived models are vital for better strategies of HCV diagnosis and treatment, and the improved designs of antivirals and vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI080734-01A1
Application #
7729965
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Koshy, Rajen
Project Start
2009-07-15
Project End
2010-06-30
Budget Start
2009-07-15
Budget End
2010-06-30
Support Year
1
Fiscal Year
2009
Total Cost
$376,250
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Lu, Ling; Wu, Tao; Xiong, Lu et al. (2016) Analysis of HCV-6 isolates among Asian-born immigrants in North America reveals their high genetic diversity and a new subtype. Virology 492:25-31
Lu, Ling; Xu, Yan; Yuan, Jie et al. (2015) The full-length genome sequences of nine HCV genotype 4 variants representing a new subtype 4s and eight unclassified lineages. Virology 482:111-6
Lu, Ling; An, Yuling; Zou, Ji et al. (2015) The evolutionary patterns of hepatitis C virus subtype 2a and 6a isolates linked to an outbreak in China in 2012. Virology 485:431-8
Li, Chunhua; Barnes, Eleanor; Newton, Paul N et al. (2015) An expanded taxonomy of hepatitis C virus genotype 6: Characterization of 22 new full-length viral genomes. Virology 476:355-63
Xiong, Huaping; Huang, Jieting; Rong, Xia et al. (2015) HLA-B alleles B*15:01 and B*15:02: opposite association with hepatitis C virus infection in Chinese voluntary blood donors. Intervirology 58:80-7
Lu, Ling; Li, Chunhua; Xu, Yan et al. (2014) Full-length genomes of 16 hepatitis C virus genotype 1 isolates representing subtypes 1c, 1d, 1e, 1g, 1h, 1i, 1j and 1k, and two new subtypes 1m and 1n, and four unclassified variants reveal ancestral relationships among subtypes. J Gen Virol 95:1479-87
Li, Chunhua; Yuan, Manqiong; Lu, Ling et al. (2014) The genetic diversity and evolutionary history of hepatitis C virus in Vietnam. Virology 468-470:197-206
Li, Chunhua; Lu, Ling; Murphy, Donald G et al. (2014) Origin of hepatitis C virus genotype 3 in Africa as estimated through an evolutionary analysis of the full-length genomes of nine subtypes, including the newly sequenced 3d and 3e. J Gen Virol 95:1677-88
Li, Chunhua; Pham, Van H; Abe, Kenji et al. (2014) Nine additional complete genome sequences of HCV genotype 6 from Vietnam including new subtypes 6xb and 6xc. Virology 468-470:172-7
Lu, Ling; Wang, Min; Xia, Wenjie et al. (2014) Migration patterns of hepatitis C virus in China characterized for five major subtypes based on samples from 411 volunteer blood donors from 17 provinces and municipalities. J Virol 88:7120-9

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