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

Area of Science:

• Immunology and Virology
• HIV/AIDS Research

Background:

• Durable treatment-free remission is a key goal for people living with HIV (PLWH).
• Elite controllers, particularly exceptional controllers with minimal or no intact HIV provirus, offer insights into cure-like immunity.

Purpose of the Study:

• To identify the immunological mechanisms underlying exceptional HIV control.
• To define the role of specific CD8+ T cell subsets and viral epitope targeting in HIV immunity.

Main Methods:

• Integration of functional epitope mapping, single-cell transcriptomics, and infected cell elimination assays.
• Flow cytometry analysis of CD8+ T cell subsets, including KIR+ CD8+ T cells, in HIV controllers and ART-suppressed individuals.
• Functional depletion assays to assess the impact of KIR+ CD8+ T cells on HIV-infected cell elimination.

Main Results:

• Exceptional HIV control is characterized by networked HIV epitope targeting and a distinct natural killer (NK)-like CD8+ T cell subset expressing killer-cell immunoglobulin-like receptors (KIR+ CD8+ T cells).
• This NK-like CD8+ T cell subset was enriched in HIV-specific T cells and transcriptionally similar to cytotoxic T cells.
• Depletion of KIR+ CD8+ T cells significantly impaired the elimination of autologous HIV-infected CD4+ T cells.

Conclusions:

• A previously unrecognized NK-like KIR+ CD8+ T cell state is a critical component of exceptional HIV immunity.
• This finding complements networked epitope targeting and provides a novel framework for developing immunotherapeutic HIV cure strategies.