14, 15 We passively immunized six chimeric mice with 1 mg/g H06-antibody and 3 days later challenged them with a 100% infectious dose of plasma-derived mED43 (104 IU/mouse). Three additional chimeric mice received the same viral dose but were injected with irrelevant antibody and served as a control group. One week after viral inoculation, all three control animals had plasma HCV RNA levels ranging between 2.18 × 105 and 4.80 × 107 IU/mL (Table 1). In contrast, all antibody-treated animals remained HCV-negative (<1,500 IU/mL). One week later, HCV RNA could be quantified in four chimeric mice with levels ranging between 2.08 × 103 and 4.25

× 107 IU/mL. At week 3, one of the animals that was negative at weeks 1 and 2 developed low titered viremia (Fig. 2A). Overall, only one of six mice selleck compound seemed to be completely protected from a heterologous mED43 challenge, but in the five infected animals the rise in viral titer was clearly delayed (Table 1). To investigate whether H06-antibodies were able to neutralize

an in vivo infection with HCV of strain mHK6a (gt6a), we treated four animals with H06-IgG as described above and challenged these mice with mHK6a (105 IU/mouse) 3 days later. Three nontreated control animals had HCV RNA levels of at least 5.43 × 104 IU/mL in the week 1 sample, increasing up to 3.34 × 107 IU/mL at week 3 (Table 1). Three of the four treated animals were HCV-negative RXDX-106 manufacturer after 1 week (<375 IU/mL). One week later HCV RNA could be detected in a second treated chimeric mouse (Fig. 2B). Three weeks after injection of the virus one of the two HCV-negative animals died spontaneously but in the remaining animal HCV RNA remained undetectable throughout the 8-week observation period (<375 IU/mL). To investigate whether the viruses that emerged in H06-treated chimeric mice contained mutations in their genome that might result in resistance to the

neutralizing antibodies, we sequenced the complete E1E2-region of HCV in H06-treated mice and in control animals and compared these sequences to that of the virus that was injected. As shown in Table 2, three Interleukin-3 receptor of the five H06-treated mice challenged with mED43 that were not protected did not have any coding mutations in the envelope region of the recovered viruses. Thus, the HCV infection observed in these animals clearly represented a failure of neutralization, and not virus escape from nAb. However, in one H06-treated mED43-infected mouse (K614), a coding mutation was observed in the E1 region compared to the inoculum and the consensus ED43 sequence (GU814265). A mixture of this mutation (M221L) and the wildtype was also observed in one of the control animals.