Alisa Huber, Albert L. Groenendijk, Adriana Navas, Nadira Vadaq, Suzanne D. E. Ruijten, Vasiliki Matzaraki, Ezio T. Fok, Aysel Gurbanova, W Vos, Marc J. T. Blaauw, Louise E. van Eekeren, Maartje Jacobs‐Cleophas, Janneke E. Stalenhoef, Marvin A. H. Berrevoets, Renate G. van der Molen, Arnold van der Meer, Marien I. de Jonge, Joost H.A. Martens, Casper Rokx, Annelies Verbon, Jan van Lunzen, Hans J. P. M. Koenen, Mihai G. Netea, André van der Ven, Leo A. B. Joosten, Jéssica Cristina dos Santos
BACKGROUND: NK cells play a key role in eliminating HIV-infected cells, but it is unclear whether there are specific NK cell receptor signatures in spontaneous HIV controllers. METHODS: We conducted a cross-sectional analysis of circulating NK cell phenotypes in people living with HIV (PLHIV), divided into spontaneous HIV controllers (HIC), normal progressors on antiretroviral therapy (non-HIC), and first-degree HIV-negative family members. Using supervised and unsupervised flow cytometry, we assessed NK cell markers and receptors. We performed an epigenetic analysis of H3K4me3 chromatin enrichment in NK cells from both HIC and non-HIC and measured IFNγ, Perforin and CD107a expression in NK cells upon stimulation with IL-2/IL-15, K562 cells, and IFNα. Additionally, we conducted a genome-wide association study (GWAS) and quantitative trait locus (QTL) mapping using data from HIC and non-HIC part of the 2000HIV study. FINDINGS: NK cells and increased expression of NKp46, NKp30, and DNAM-1. The genetic association between protective MHC class I alleles and the NK cell receptor KIR2DL2/3 supports a genetic predisposition to HIV control. Unsupervised clustering identified an HIV-induced NK cell population, separate from CMV-induced NK cells. Epigenetic analysis revealed greater H3K4me3 marks in genes involved in immune response pathways, including IFNα, IL-15, and IL-2. The memory-like NK cell subpopulation was characterised by elevated expression of NKG2C and ILT2, with reduced KIR2DL2/3 in HIC. These memory NK cells were more responsive to stimulation with IFNα, resulting in increased production of IFNγ in HIC. INTERPRETATION: These results suggest that spontaneous HIV control is associated with an NK cell memory phenotype, shaped by HIV infection, epigenetic modifications, and genetic factors. FUNDING: The authors are part of the 2000HIV study, which is supported by ViiV Healthcare.