Hepatitis C is a relatively common disease that is associated with a very large disease burden. Over 170 million persons are infected worldwide and at risk for the long-term complications of the disease—cirrhosis and liver cancer—and here in the U.S., there are about 10,000 deaths annually due to these complications. However, it is only in the past two years that we have acquired the laboratory tools needed to propagate the virus in cell culture. This is a very important advance to the field, because this new technology facilitates the development and testing of new vaccines or new antiviral therapies.

“The article is a systematic synthesis of existing knowledge in relation to a theory that has not been applied to human studies before.”

Several groups of authors published reports concerning the ability of the novel Japanese JFH1 strain of HCV to replicate in cultured cells in the months leading up to our paper. This was a very important finding, but unfortunately the JFH1 virus is a genotype 2a virus, and thus, very different from the most prevalent strains of hepatitis C virus that are most often associated with fatal liver disease and liver cancer. Genotype 1 viruses account for about 70% or more of all hepatitis C virus infections in the U.S., and are by far the most difficult for clinicians to treat; genotype 2 viruses, on the other hand, are typically less than 20% of all viruses, and respond very well to interferon-based therapies, usually ending with a cure following the interferon-based treatments available today.

In contrast to the JFH1 virus, our paper describes the novel genotype 1a virus, H77S, that we produced and showed was capable of growing in cultured human cells. While not as efficient at replicating in these cells as the JFH1 virus, it is much more representative of the genotype 1 hepatitis C virus strains that physicians commonly see in their patients. Thus, in many ways, our virus is a much better model than the JFH1 virus.

Really, all of the above. Our success in getting the H77S genotype 1a hepatitis C virus to grow in cultured cells required a sustained discovery and development process that rested heavily on the work of many others who have gone before us in working with this particular strain of HCV.

Now that we have a genotype 1a hepatitis C virus that replicates in cultured cells, we have a very useful laboratory tool. The virus provides a very good experimental system to investigate how it replicates (makes copies of itself) in the infected host.

We can use this cell culture-infectious hepatitis C virus, which we think undergoes all the normal steps in the life-cycle of hepatitis C virus, to better understand the molecular mechanisms by which the virus reproduces. We can use it to study how the virus enters into host cells, and how it assembles itself and gets out, and how the cell attempts to cope with all this.

A better understanding of all these steps will allow us to develop novel and more effective therapies that will interrupt these key viral processes and that can potentially replace the current therapeutic mainstay, interferon, which, at best, is effective in eliminating the virus in only about 50% of people with this most difficult type of hepatitis C to treat.

My lab has been working in this field for just about 30 years, and we have had a very strong interest in hepatitis C since the virus genome was identified around 1989. Getting the virus to grow in cell culture has always been an elusive dream to those in the field, however. This can be easily done with many other types of viruses, like herpesviruses and polioviruses, but for some reason this is not the case with hepatitis viruses that normally grow in very specialized liver cells, and this is especially the case with hepatitis C virus.

We had to identify the right mutations to make this virus go, and the right cell type, and the right conditions, and the right methods to detect its presence in infected cells. It would be incorrect to say that there wasn’t a significant amount of luck involved, but it was coupled with a lot of hard work on the part of my colleagues to make this happen.

We are using this advance to determine how the immune system (antibodies) "sees" the virus functionally, and how new experimental inhibitors of hepatitis C virus replication work.

We continue to make improvements in our ability to culture this virus, and I suspect that the methods and the virus strain that we described in our paper will play an important role in bringing new therapies and vaccines into the clinic.

Using this virus is also helping us elucidate the molecular mechanisms that the virus exploits in promoting the development of liver cancer in chronically infected persons—understanding these mechanisms may allow us to block them, or possibly even reverse them, at some point in the future.

If our work helps materially in preventing or alleviating the disease and suffering associated with chronic hepatitis C, cirrhosis, and liver cancer, these are implications enough for us!