Mild HIV-specific selective forces overlaying natural CD4+ T cell dynamics explain the clonality and decay dynamics of HIV reservoir cells

作者：Daniel B. Reeves, Danielle Rigau, Arianna Romero, Hao Zhang, Francesco R. Simonetti, Joseph Varriale, Rebecca Hoh, Li Zhang, Kellie N. Smith, Luis J. Montaner, Leah H. Rubin, Stephen J. Gange, Nadia R. Roan, Phyllis C. Tien, Joseph B. Margolick, Michael J. Peluso, Steven G. Deeks, Joshua T. Schiffer, Janet D. Siliciano, Robert F. Siliciano, Annukka A.R. Antar · 发表于：Cell Systems · 年份：2025 · DOI：10.1016/j.cels.2025.101402 · 被引用次数：2 · 研究领域：HIV Research and Treatment、Immune Cell Function and Interaction

To determine whether HIV persistence arises from the natural dynamics of memory (m)CD4+ T cells, we compare clonal dynamics of HIV proviruses and mCD4+ T cells from the same people living with HIV (PWH) on antiretroviral therapy and from matched HIV-seronegative people (N = 51). HIV proviruses are more clonal than mCD4+ T cells but similarly clonal to antigen-specific cells. Increasing reservoir clonality over time and differential decay of intact and defective proviruses are not explained by mCD4+ T cell kinetics alone. We develop and validate a stochastic model trained on 10 quantitative data metrics, which shows that negative selection against HIV-infected cells is necessary to explain all metrics. We estimate the strength of negative selection, finding that death of cells harboring intact and defective proviruses is infrequently (∼6% and ∼2% on average) due to HIV-specific factors. Thus, our data indicate that HIV persistence is mostly, but not entirely, driven by natural mCD4+ kinetics.