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

Authors

Alrubayyi, A., Traunbauer, A. K., Crain, C. R., Bhattacharyya, S., Collins, D. R., Huang, H., Kaseke, C., Arshad, U., Lian, X., Vijayakumar, A., Getz, M. A., Lichterfeld, M., Yu, X., Walker, B. D., Lauer, G. M., Gaiha, G. D.

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.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 09 Jul 2026.

Stats

1-terrible, 9-excellent. How would you rate this preprint? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.