Functional impairment of HIV-specific CD8+ T cells precedes aborted spontaneous control of viremia

Abstract

Spontaneous control of HIV infection has been repeatedly linked to antiviral CD8+ Tcells but is not always permanent. To address mechanisms of durable and aborted control of viremia, we evaluated immunologic and virologic parameters longitudinally among 34 HIV-infected subjects with differential outcomes. Despite sustained recognition of autologous virus, HIV-specific proliferative and cytolytic Tcell effector functions became selectively and intrinsically impaired prior to aborted control. Longitudinal transcriptomic profiling of functionally impaired HIV-specific CD8+ Tcells revealed altered expression of genes related to activation, cytokine-mediated signaling, and cell cycle regulation, including increased expression of the antiproliferative transcription factor KLF2 but not of genes associated with canonical exhaustion. Lymphoid HIV-specific CD8+ Tcells also exhibited poor functionality during aborted control relative to durable control. Our results identify selective functional impairment of HIV-specific CD8+ Tcells as prognostic of impending aborted HIV control, with implications for clinical monitoring and immunotherapeutic strategies.