NK-like and networked CD8 + T cell immunity mediates exceptional HIV control

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 1,2 . However, rare reservoir-defined exceptional controllers within the spectrum of elite control 3–5 , characterized by the absence of intact provirus or proviruses confined to transcriptionally repressed genomic regions 6 , 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.