Lai's team's studies of interferon resistance focused on E2, a protein component of HCV?s outer sheath, or envelope. The investigators found that E2 from all genotype 1 HCV (the most common form of HCV in the United States), which is essentially resistant to interferon, contains a 12 amino acid sequence that is identical to the site that PKR phosphorylates, both on itself and on eIF2a .
Further experiments by Lai and his colleagues confirmed that the E2 protein not only blocks PKR phosphorylation in cells, but blocks PKR's ability to inhibit protein synthesis, too. The results of these studies appeared in the July 2, 1999, issue of the journal Science.
"Our findings show that E2 inhibits interferon by targeting PKR and eIF2a ," explained Lai. "It does so by providing a site that PKR will bind to instead of its normal targets for phosphorylation."
By identifying E2's target, Lai believes that pharmaceutical researchers will now be able to develop strategies to overcome the virus' ability to neutralize interferon. This will not be an easy task since HCV's genome is highly heterogeneous, or varied. To make matters worse, the E2 gene of HCV is probably the most heterogeneous gene of all. "The consequence of the genetic diversity of HCV is a virus that has the ability to escape the immune surveillance of its host, leading to a high rate of chronic infections and a lack of protective immunity in individuals exposed repeatedly to the virus," said Robert Purcell, an HCV researcher at the National Institutes of Health. Fortunately, the region of E2 that bears resemblance to PKR is a relatively invariable sequence, said Lai.
Lai believes that this extensive genetic diversity, besides creating clinical
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
2-Jul-1999