Blight - adapt. HCV rep - REPORTS 10 J Anderson I Lampl I...

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10. J. Anderson, I. Lampl, I. Reichova, M. Carandini, D. Ferster, Nature Neurosci. 3 , 617 (2000). 11. B. W. Knight, J. Gen. Physiol. 59 , 734 (1972). 12. D. J. Heeger, Visual Neurosci. 9 , 427 (1992). 13. We repeated the simulations illustrated in Fig. 3. Instead of using a constant-amplitude noise for all orientations and contrasts in the simulation, howev- er, we used the values of Fig. 2G. The simulations resulted in contrast invariance indistinguishable from that shown in Fig. 3, E and F. 14. Spike threshold in the model, in some cases, was lowered below its measured value in order to obtain nonzero spike rates for predictions from averaged traces without added noise. In each cell, the same value for spike threshold was used for all three predictions. 15. D. C. Somers, S. B. Nelson, M. Sur, J. Neurosci. 15 , 5448 (1995). 16. R. Ben-Yishai, R. L. B. Or, H. Sompolinsky, Proc. Natl. Acad. Sci. U.S.A. 92 , 3844 (1995). 17. H. Sompolinsky, R. Shapley, Curr. Opin. Neurobiol. 7 , 514 (1997). 18. I. Lampl, I. Reichova, D. Ferster, Neuron 22 , 361 (1999). 19. J. M. Alonso, W. M. Usrey, R. C. Reid, Nature 383 , 815 (1996). 20. D. S. Reich, J. D. Victor, B. W. Knight, T. Ozaki, E. Kaplan, J. Neurophysiol. 77 , 2836 (1997). 21. A. Bulsara, E. W. Jacobs, T. Zhou, F. Moss, L. Kiss, J. Theor. Biol. 152 , 531 (1991). 22. K. Wiesenfeld, F. Moss, Nature 373 , 33 (1995). 23. N. Ho, A. Destexhe, J. Neurophysiol. 84 , 1488 (2000). 24. Supported by grant R01 EY04726 from the National Eye Institute. We thank K. D. Miller, T. W. Troyer, M. Stryker, and M. Carandini for valuable discussions. 13 September 2000; accepted 20 October 2000 Efficient Initiation of HCV RNA Replication in Cell Culture Keril J. Blight, 1 Alexander A. Kolykhalov, 1 Charles M. Rice 1,2 * Hepatitis C virus (HCV) infection is a global health problem affecting an estimated 170 million individuals worldwide. We report the identification of multiple independent adaptive mutations that cluster in the HCV nonstructural protein NS5A and confer increased replicative ability in vitro. Among these adaptive mutations were a single amino acid substitution that allowed HCV RNA replication in 10% of transfected hepatoma cells and a deletion of 47 amino acids encompassing the interferon (IFN) sensitivity determining region (ISDR). Independent of the ISDR, IFN- a rapidly inhibited HCV RNA replication in vitro. This work establishes a robust, cell-based system for genetic and functional analyses of HCV replication. HCV ( 1 ) typically evades clearance by the host’s immune system, allowing the establish- ment of a persistent infection in at least 70% of infected individuals. HCV-associated end-stage liver disease is now the leading cause of liver transplantation in the United States. Most pa- tients treated with IFN alone either fail to re- spond or do not mount a sustained response. In Japanese patients, the amino acid sequence in a defined region of NS5A, designated the ISDR, appears to correlate with the effectiveness of IFN treatment. However, this association is substantially weaker or absent in patients infect- ed with genotype 1a HCV strains or European patients infected with genotype 1b strains. Al- though considerable genetic heterogeneity ex- ists among different HCV isolates, genotypes 1a and 1b are the most prevalent worldwide ( 2 ).
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