Abstract
HIV latency is the chief obstacle to eradicating HIV but is widely
believed to be an evolutionary accident providing no lentiviral fitness
advantage. However, findings of latency being “hardwired” into HIV’s
gene-regulatory circuitry appear inconsistent with latency being an
evolutionary accident, given HIV’s rapid mutation rate. Here, we propose
that latency is an evolutionary “bet-hedging” strategy whose
frequency has been optimized to maximize lentiviral transmission by
reducing viral extinction during mucosal infections. The model
quantitatively fits the available patient data, matches observations of
high-frequency latency establishment in cell culture and primates, and
generates two counterintuitive but testable predictions. The first
prediction is that conventional CD8-depletion experiments in
SIV-infected macaques increase latent cells more than viremia. The
second prediction is that strains engineered to have higher replicative
fitness-via reduced latency-will exhibit lower infectivity in
animal-model mucosal inoculations. Therapeutically, the theory predicts
treatment approaches that may substantially enhance
“activate-and-kill” HIV-cure strategies.
