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Such efforts are critically important in devising better methods for managing a disease that chronically infects approximately 200 million people worldwide. The most effective treatment for hepatitis C, interferon-based therapy, eradicates the virus less than 50 percent of the time and causes debilitating side effects. For many years, hepatitis C research was handicapped by scientists inability to produce infectious hepatitis C virus in the laboratory. Other laboratories have recently achieved successful culture of genotype 2a viruses that are less common and more readily treated by interferon. (Scientists group hepatitis C viruses into six major genetic categories called genotypes.) However, laboratory growth of a genotype 1 virus has been an elusive goal long sought by many laboratories.
More than 50 percent of hepatitis C patients are infected with genotype 1 viruses, which are much less likely to respond to interferon, said Dr. Stanley M. Lemon, director of UTMBs Center for Hepatitis Research and senior author of a paper describing the work, which will be published online by the Proceedings of the National Academy of Sciences this week. A cell-culture infectious variant of genotype 1 virus has been urgently needed, and thats what weve developed.
Lemons group, including assistant professor MinKyung Yi and postdoctoral fellow Rodrigo Villanueva, started with a genotype 1 hepatitis C virus known to be highly infectious in chimpanzees. First, we identified five mutations that enhanced the ability of this virus to replicate within cultured human liver cells, and then we were able to demonstrate that a virus containing these critical mutations could make virus particles that could infect other cells, said lead author Yi. This is an exciting finding.
For reasons still to be explained, the mutated genotype 1 hepatitis C virus infects cultured cells less efficiently than genotype 2a viruses used in prior studies. However, the UTMB genotype 1 virus is sufficiently infectious to enable the testing of candidate antiviral drugs that act at any step of the viral life cycle, and will facilitate the efforts of researchers to identify the receptor molecule on the cell surface used by the virus to gain entrance to cells.
The scientists also were able to determine that serum taken from people known to be infected with genotype 1 hepatitis C neutralized the genotype 1 virus in culture, showing a close similarity in immune recognition of the cell-culture virus and a common variety circulating in the general population. Genotype 2a virus was not neutralized by these serum samples, however, indicating a significant immunological difference between the two hepatitis C genotypes and suggesting an absence of strong cross-genotype immunity.
This cell culture system should be very useful in helping us understand how the virus gets into cells, which could lead to the development of entry inhibitor drugs like those developed for HIV, Lemon said. Its already giving us a better understanding of hepatitis C virus biology.
Source: University of Texas Medical Branch at Galveston