A mechanistic basis for CD8+ T cell expansion sensitivity as a predictor of HIV post-treatment control
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…
The pursuit of a cure for HIV-1 infection hinges on comprehending why certain individuals manage to control viral rebound following the discontinuation of antiretroviral therapy (ART). Recent investigations have pinpointed responding CD8+ T cells, characterized by the presence of Ki-67 and the transcription factor TCF-1, as indicators of post-treatment viral control.
However, the underlying mechanism explaining this correlation has not been elucidated. Employing a theoretical framework developed by Conway and Perelson, researchers fitted mechanistic models to viral load and CD8+ T cell data from 9 participants in a combination immunotherapy trial, commencing following ART interruption. While the original measurements of Ki-67 and TCF-1 were not utilized for model fitting, the derived effector cell expansion sensitivity, representing the responsiveness of effector expansion to minimal antigen levels, exhibited a robust linear correlation with Ki-67 and TCF-1 levels at the time of viral rebound (Pearson's r ≈ 0.8).
Expanding on this finding, the researchers mathematically demonstrated that the post-rebound viral load threshold is inversely proportional to the effector cell expansion sensitivity, thereby demonstrating a strong association with cycling (Ki-67+) CD8+ T cells (Pearson's r ≈ -0.8) and a specific subset expressing TCF-1 (Pearson's r ≈ -0.9) at viral rebound.
Consequently, individuals who possess a greater proportion of CD8+ T cells responding to viral rebound and a higher prevalence of TCF-1 expressing cells among the responding subset attain substantially lower viral set points due to an augmented effector cell expansion sensitivity. This mechanism aligns with previous modeling conducted in the absence of intervention within an ART-insensitive context, implying its potential applicability to a wider range of rebound scenarios.
The findings offer a mechanistic rationale for the observed clinical correlations between Ki-67+ responding CD8+ T cells and their TCF-1-expressing subset, serving as potential early biomarkers for the success of HIV immunotherapy.
Written by urgent.news from bioRxiv's reporting — not their text. Machine-written — may contain errors; check the original before relying on it.
