The hepatitis C virus (HCV) is the major cause of chronic addition, we recently reported a close correlation be-non-A, non-B hepatitis, a disease that seldom resolves spontween the number of mutations in amino acid sequences taneously and that can progress to cirrhosis and hepatocellu-2209 to 2248 of the nonstructual protein 5A gene lar carcinoma over several decades. 1 The development of ef-(NS5A2209-2248) of HCV-1b and the response to IFN-a. fective treatments to eradicate HCV infection is of great In the present study, we analyzed these viral factors in medical importance. relation to the efficacy to IFN-b, another type I IFN. TheInterferon alfa (IFN-a) a type I IFN, has been used to treat pretreatment sera of 40 patients treated with IFN-b in-chronic hepatitis C throughout the world since the first report travenously at 6 MU daily for 42 days were studied. HCV of its beneficial effects in 1986. 2 IFN-b is also a type I IFN genotypes, serum HCV-RNA levels, and the amino acid that is commonly used in the treatment of acute and chronic sequence of NS5A2209-2248 in HCV-1b were determined. hepatitis C in Japan. [3][4][5] It has been believed that type I IFNs A sustained complete response to IFN therapy occurred bind to the same receptor; however, recent evidence suggests in none of the ten patients with the wild-type HCV-1b the existence of a second receptor-associated protein that is who had an NS5A2209-2248 sequence identical to the involved specifically in the IFN-b signaling pathway. 6 Inprototype HCV-1b and in none of the six patients with deed, in vitro experiments have shown that different type I the intermediate-type HCV-1b that had 1 mutation. In IFNs induce different biological responses. 7,8 Thus, IFN-a contrast, complete responses occurred in the following: and IFN-b may exhibit different characteristics in the treat-4 of 6 patients with the mutant-type HCV-1b that had ment of chronic hepatitis C. five to ten mutations; 6 of 13 patients with genotype 2aThe majority of clinical trials in hepatitis C have employed of HCV (HCV-2a); and 2 of 5 patients with genotype 2b recombinant or natural IFN-a and have shown that HCV of HCV (HCV-2b). Among patients with the mutant-type genotypes and serum HCV-RNA levels correlate with long-HCV-1b or genotype 2 of HCV (HCV-2) the rate of com-term beneficial responses to IFN-a. Thus, genotype 1b of HCV plete response was significantly higher (12 of 24 vs. 0 of (HCV-1b) has been found to be more resistant to IFN-a than 16 patients, P õ .001) and HCV-RNA levels were signifi-was genotype 2 of HCV (HCV-2), and patients with high cantly lower (4.5 [4.0-6.5] vs. 6 [4.5-6.5] log copies/mL, me-HCV-RNA levels were found to be more resistant to IFN-a dian [range]; P õ .001) compared with patients with the than were those with low HCV-RNA levels. 9-17 Furthermore, wild-or the intermediate-type HCV-1b. Patients with the we reported recently that the sensitivity to IFN-a in HCVmutant-type HCV-1b or HCV-2 whose HCV-RNA levels 1b correlates closely with the number of mutations in the ...

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Embryonic stem (ES) cells have the ability to generate teratomas when transplanted into immunodeficient mice, but conditions affecting the generation remain to be elucidated. Nonhuman primate cynomolgus ES cells were transplanted into immunodeficient mice under different conditions; the number of transplanted cells, physical state (clumps or single dissociated cells), transplant site, differentiation state, and immunological state of recipient mice were all varied. The tumorigenicity was then evaluated. When cynomolgus ES cells were transplanted as clumps into the lower limb muscle in either nonobese diabetic/severe combined immunodeficiency (NOD/SCID) or NOD/SCID/gammac(null) (NOG) mice, teratomas developed in all the animals transplanted with 1 x 10(5) or more cells, but were not observed in any mouse transplanted with 1 x 10(5) cells. However, when the cells were transplanted as dissociated cells, the number of cells necessary for teratomas to form in all mice increased to 5 x 10(5). When the clump cells were injected subcutaneously (instead of intramuscularly), the number also increased to 5 x 10(5). When cynomolgus ES cell-derived progenitor cells (1 x 10(6)), which included residual pluripotent cells, were transplanted into the lower limb muscle of NOG or NOD/SCID mice, the incidence of teratomas differed between the strains; teratomas developed in five of five NOG mice but in only two of five NOD/SCID mice. The incidence of teratomas varied substantially depending on the transplanted cells and recipient mice. Thus, considerable care must be taken as to tumorigenicity.