Transforming dysfunctional CD8+ T cells into natural controller-like CD8+ T cells: can TCF-1 be the magic wand?

HIV infection results in defective CD8+ T cell functions that are incompletely resolved by antiretroviral therapy (ART) except in natural controllers, who have functional CD8+ T cells associated with viral control. In this issue of the JCI, Perdomo-Celis et al. demonstrated that targeting the Wnt/transcription factor T cell factor 1 (Wnt/TCF-1) pathway in dysfunctional CD8+ T cells led to gains in stemness phenotype, metabolic quiescence, survival potential, response to homeostatic γ-chain cytokines, and antiviral capacities, similar to profiles of functional CD8+ T cells in natural controllers. Although reprogramming might not sufficiently reverse the imprinted dysfunction of CD8+ T cells in HIV infection, these findings outline the Wnt/TCF-1 pathway as a potential target to reprogram dysfunctional CD8+ T cells in efforts to achieve HIV remission.