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.Author summary: When people with HIV take effective treatment, the virus can no longer be detected in the blood, but a small number of infected cells persist in a dormant state, forming what is known as the latent reservoir. This hidden pool of virus is the main barrier to a cure because it can reactivate if treatment is stopped. In this study, we developed a mathematical model that simulates the behavior of individual infected cell lineages, or “clones,” to understand how the reservoir changes over time. Our model incorporates two key forces: the chance that a latent virus reactivates and the signals from the immune environment that drive infected cells to divide. Our results show that the reservoir becomes dominated by a few large, long-lived clones that rarely reactivate, while smaller, more dynamic clones are gradually lost. Importantly, we find that low-level viral replication during treatment does not necessarily lead to viral evolution — a distinction that challenges common assumptions and helps explain why the virus remains genetically stable in individuals on long-term treatment. Our findings suggest that eliminating the reservoir may require strategies that go beyond reactivation, targeting the large and persistent clones that silently maintain the infection.