Clonal heterogeneity and antigenic stimulation shape persistence of the latent reservoir of HIV

Drug treatment can control HIV-1 replication, but it cannot cure infection. This is because of a long-lived population of quiescent infected cells, known as the latent reservoir (LR), that can restart active replication even after decades of successful drug treatment. Many cells in the LR belong to highly expanded clones, but the processes underlying the clonal structure of the LR are unclear. Understanding the dynamics of the LR and the keys to its persistence is critical for developing an HIV-1 cure. Here we develop a quantitative model of LR dynamics that fits available patient data over time scales spanning from days to decades. We show that the interplay between antigenic stimulation and clonal heterogeneity shapes the dynamics of the LR. In particular, we find that large clones play a central role in long-term persistence, even though they rarely reactivate. Our results could inform the development of HIV-1 cure strategies.