Mechanism for evolution of diverse autologous antibodies upon broadly neutralizing antibody therapy of people with HIV

Antiretroviral therapy (ART) inhibits Human Immunodeficiency Virus (HIV) replication to maintain undetectable viral loads in people living with HIV, but does not result in a cure. Due to the significant challenges of lifelong ART for many, there is strong interest in therapeutic strategies that result in cure. Recent clinical trials have shown that administration of broadly neutralizing antibodies (bnAbs) when there is some viremia can lead to ART-free viral control in some people; however, the underlying mechanisms are unclear. Our computational modeling shows that bnAbs administered in the presence of some viremia promote the evolution of autologous antibodies (aAbs) that target diverse epitopes of HIV spike proteins. This “net” of polyclonal aAbs could confer control since evasion of this response would require developing mutations in multiple epitopes. Our results provide a common mechanistic framework underlying recent clinical observations upon bnAb/ART therapy, and they should also motivate and inform new trials.