A key goal in HIV-1 cure research is to understand why some individuals control viral rebound after stopping antiretroviral therapy (ART). Recent human studies have identified responding CD8+ T cells expressing Ki-67 and the transcription factor TCF-1 as correlates of post-treatment control, but the mechanistic basis of this association remains unclear. Using the theoretical framework of Conway and Perelson, we fit mechanistic within-host models to viral load and CD8+ T cell data from 9 individuals in a combination immunotherapy trial following ART interruption. Although Ki-67 and TCF-1 measurements were not used for fitting, the inferred effector cell expansion sensitivity, i.e., the responsiveness of effector expansion to low antigen levels, shows a strong linear relationship with Ki-67 and TCF-1 levels at rebound (Pearsons r {approx} 0.8). Building on this, we show analytically that the post-rebound viral load set point is inversely proportional to the effector cell expansion sensitivity, and thus strongly correlates with cycling (Ki-67+) CD8+ T cells (r {approx} -0.8) at rebound, and a subset that expresses TCF-1 (r {approx} -0.9). In effect, individuals with a larger proportion of CD8+ T cells responding to viral rebound, and a greater representation of TCF-1 expressing cells within the responding subset, achieve markedly lower viral set points through a higher effector cell expansion sensitivity. This mechanism is consistent with prior modeling in a non-intervention ATI setting, suggesting it may generalize across more rebound contexts. Our results provide a mechanistic explanation why both Ki-67+ responding CD8+ T cells and their TCF-1-expressing subset predict post-treatment control, linking clinical correlation to its underlying cause and highlighting Ki-67 and TCF-1 as potential early biomarkers of HIV immunotherapy success.
Phan, T., Pagane, N., Kreig, J. A. F., Marc, A., Locke, M., Peluso, M. J., Sandel, D. A., Deitchman, A. N., Rutishauser, R. L., Deeks, S. G., Ke, R., Ribeiro, R. M., Perelson, A. S.
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