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The human monoclonal antibodies (mAb) 2F5, 2G12, and 4E10 are three of the most broadly neutralizing antibodies against HIV-1. Although they have been shown to prevent de novo infection in vivo, their potential for treatment of chronic infection is less clear. One major obstacle may be the emergence of resistant viruses during mAb treatment.To assess whether escape mutants can be generated in vitro which are resistant to all three mAbs, two neutralization-sensitive T-cell line-adapted viruses and two primary isolates were passaged in the presence of increasing concentrations of 2F5, 2G12, 4E10, and a 1: 1: 1 mixture. To get insight into viral escape in vivo, viruses were isolated from eight patients treated with repeated infusions of 2F5/2G12/4E10.In vitro, viruses resistant to a single mAb emerged after 3–22 weeks. Generation of viruses resistant to the triple-combination was a slower process characterized by recurrent loss of virus replication. Some generated triple-resistant viruses seemed to be impaired in their replicative fitness. Neutralization resistance to 2F5 and partly 4E10 could be attributed to amino acid mutations in the mAb epitopes, but not for 2G12. In vivo, none of the patients developed detectable viruses that escaped neutralization by all three mAbs within the 77-day observation period. Virus escape occurred only to 2G12 in three patients.In summary, the findings of the in vivo study and the difficulty in generating multi-resistance in vitro together with the fact that some generated viruses seemed to have impaired replication fitness indicate that 2F5, 2G12, and 4E10 may be useful for therapy in HIV-1 infection.