Abstract
Many broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus type 1 (HIV-1) were shown effective in animal models, and are currently evaluated in clinical trials. However, use of these antibodies in humans is hampered by the rapid emergence of resistant viruses. Here we show that soft-randomization can be used to accelerate the parallel identification of viral escape pathways. As a proof of principle, we soft-randomized the epitope regions of VRC01-class bNAbs in replication-competent HIV-1 and selected for resistant variants. After only a few passages, a surprisingly diverse population of antibody-resistant viruses emerged, bearing both novel and previously described escape mutations. We observed that the escape variants resistant to some VRC01-class bNAbs are resistant to most other bNAbs in the same class, and that a subset of variants was completely resistant to every well characterized VRC01-class bNAB, including VRC01, NIH45-46, 3BNC117, VRC07, N6, VRC-CH31, and VRC-PG04. Thus, our data demonstrate that soft randomization is a suitable approach for accelerated detection of viral escape, and highlight the challenges inherent in administering or attempting to elicit VRC01-class antibodies.
Highlights
A large number of potent broadly neutralizing antibodies have been generated from human immunodeficiency virus type 1 (HIV-1)-infected individuals
Several potent antibodies against human immunodeficiency virus type 1 (HIV-1) have been evaluated in clinical trials
Such information is available for some antibodies from clinical trials, and other mutations have been observed in animal models or selected in cell culture, only a limited number of escape variants have been described for any given antibody or combination of antibodies
Summary
A large number of potent broadly neutralizing antibodies (bNAbs) have been generated from HIV-1-infected individuals (reviewed in [1,2,3,4,5]). To use bNAbs in humans or to design vaccines based on their epitopes, it is essential to understand how viruses can escape them Such information is available for some antibodies from clinical trials, and other mutations have been observed in animal models or selected in cell culture, only a limited number of escape variants have been described for any given antibody or combination of antibodies. This small number is a consequence of inefficient process by which resistant variants emerge. To accumulate a meaningful number of escape mutations, this process needs to be repeated great many times or in many individuals or animals
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