Abstract

Durable treatment-free remission remains a defining goal for people living with HIV (PLWH). Studies of spontaneous elite controllers have revealed that functional CD8+ T cells targeting structurally networked viral epitopes can mediate durable viral suppression. However, rare reservoir-defined exceptional controllers within the spectrum of elite control, characterized by the absence of intact provirus or proviruses confined to transcriptionally repressed genomic regions, provide a unique opportunity to define mechanisms of cure-like immunity. Here, we integrate functional epitope mapping, single-cell transcriptomics, and infected cell elimination assays to identify networked HIV epitope targeting and a natural killer (NK)-like killer-cell immunoglobulin-like receptor (KIR)+ CD8+ T cell subset as key features of exceptional control. This NK-like subset was selectively enriched within HIV-specific, but not CMV-specific, CD8+ T cells from controllers, and was transcriptionally similar to highly cytotoxic subsets within the broader KIR+ CD8+ T cell compartment. Flow cytometry revealed increased frequencies of KIR+ CD8+ T cells in exceptional controllers relative to antiretroviral therapy (ART)-suppressed individuals, and unexpectedly, enrichment of dual KIR+ NKG2A+ CD8+ T cells. Functional depletion of KIR+ CD8+ T cells significantly impaired the elimination of autologous HIV-infected CD4+ T cells, despite preserved recognition by proliferative networked HIV-specific CD8+ T cells. These findings thereby identify an NK-like KIR+ CD8+ T cell state as a previously unrecognized component of exceptional HIV immunity that complements networked epitope targeting, providing a novel framework for immunotherapeutic HIV cure strategies.