Title : In vivo evolution of a transmitted/founder HIV-1 strain that is highly resistant to broadly neutralizing antibodies
Abstract:
Background
Envelope glycoproteins (Envs) of human immunodeficiency virus type I (HIV-1) mediate viral entry and are the sole target of neutralizing antibodies. Envs of most primary HIV-1 strains prefer to be in a closed conformation (State 1) and occasionally sample downstream conformational states (State 2 and State 3). Thus, current knowledge guides immunogen design towards mimicking the Env closed conformation as the preferred target for eliciting broadly neutralizing antibodies (bnAbs). Ideally, a vaccine for HIV-1 prevention should elicit bnAbs that can block the transmission of transmitted/founder (T/F) HIV-1 strains, which are a subset of HIV-1 strains that can cross the mucosal bottleneck and establish HIV-1 infection in vivo.
Methods
Here we studied different T/F strains that have been previously published and identified one T/F strain, CH040, that is highly resistant to bnAbs. We reconstructed the post-transmission evolutionary pathway of CH040 in vivo by building pseudoviruses based on consensus viral sequences at different time points during CH040 evolution in the infected individual. Consensus viral sequences were determined by analyzing available sequences from the HIV-1 database that span more than 4 years of viral evolution. We used reconstructed pseudoviruses to study the evolution of HIV-1 Env function and sensitivity to Env ligands.
Results
Evolved CH040 viruses were less sensitive than CH040 to cold and soluble HIV-1 receptor (CD4), and became resistant to the 19b antibody, which preferentially recognizes a more open Env conformations. All of which correlate with the evolution of a more closed Env state. These changes were associated with alterations in CH040 sensitivity to several bnAbs during viral evolution under the pressure of autologous antibody response in the infected individual.
Conclusion
Our results provide insights into HIV-1 evolution in vivo and evidence for the continuous range of Env conformational states. These findings can aid the development of new strategies to improve bnAb immunotherapy and Env-based immunogen design.