Date Published: August 20, 2018
Publisher: Public Library of Science
Author(s): Yuka Otsuka, Kimberly Schmitt, Brian D. Quinlan, Matthew R. Gardner, Barnett Alfant, Adrian Reich, Michael Farzan, Hyeryun Choe, Alexandra Trkola.
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.
A large number of potent broadly neutralizing antibodies (bNAbs) have been generated from HIV-1-infected individuals (reviewed in [1–5]). Many of these bNAbs, including 2F5, 4E10, PGT121, VRC01, 3BNC117 and 10–1074, have been or will be evaluated in clinical trials [6–12]. A number of animal studies have shown that administration of bNAbs can prevent infection, and reduce viral loads in an established infection [13–22]. Previous human studies also show that bNAbs can reduce viral loads or delay viral rebound upon treatment interruption [6–8, 11, 12, 23]. However, HIV-1 generally escapes these bNAbs when they are administered to infected animals or humans [6–8, 11–15, 17, 18, 20, 21, 23–26].
Most bNAbs are able to neutralize majority of known HIV-1 isolates in vitro and prevent a new infection or control an established infection in animal studies. It is well established, however, that resistant viruses easily emerge in vitro and in vivo in the presence of these antibodies (reviewed in [1, 4]). While much effort is focused on using passively administered bNAbs and eliciting bNAbs through vaccination, less effort has been dedicated to understanding how viral escape will impact the utility of those approaches. Comprehensive insight into the ways HIV-1 can escape bNAbs, and methods by which this escape potential could be rapidly assessed, are critical to the use of bNAbs in humans. Without such insight, it is difficult to determine whether an antibody will be therapeutically useful, how it might be improved, whether it would work best in concert with other antibodies or antiviral drugs, or whether its epitope would be a useful target for a therapeutic or prophylactic vaccine. Most importantly, such information is necessary to determine whether the use of bNAbs in humans will easily promote emergence and spread of resistant variants.