Mechanism for evolution of antibodies in response to HIV broadly neutralizing antibody therapy

The immune system has evolved mechanisms to generate diverse responses in the face of variant viral strains. For example, sequential immunization with the same virus can generate antibodies that target distinct epitopes (regions) of the spike protein. Diverse responses emerge because of feedback regulation of the recall response by pre-existing antibodies. We employ stochastic simulations of B cell dynamics that incorporate these feedback loops in order to study the evolution of antibodies in people living with HIV who have been treated with broadly neutralizing antibodies (bnAbs). bnAbs neutralize diverse strains and inhibit viral replication, keeping viral load low. Recent clinical trials have shown that when bnAbs are administered while some virus is present, some individuals maintain control of the virus long after treatment is interrupted. Our model explains how bnAbs can promote the evolution of new antibodies that target diverse epitopes during the treatment phase. In order to escape this antibody "net", the virus would have to develop escape mutations in many epitopes, thus delaying or preventing viral rebound. Our results provide mechanistic underpinnings of exciting new clinical data and may motivate new trials. More broadly, our work suggests that the immune system's natural tendency towards creating diverse responses could be harnessed for cure.