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.
journal_name
PLoS Pathogjournal_title
PLoS pathogensauthors
Otsuka Y,Schmitt K,Quinlan BD,Gardner MR,Alfant B,Reich A,Farzan M,Choe Hdoi
10.1371/journal.ppat.1007238subject
Has Abstractpub_date
2018-08-20 00:00:00pages
e1007238issue
8eissn
1553-7366issn
1553-7374pii
PPATHOGENS-D-18-00974journal_volume
14pub_type
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