HIV-1 infection of macrophages differentially primes NK-cell cytotoxicity and proinflammatory cytokine production
Natural killer (NK) cells are innate cytotoxic lymphocytes with antiviral functions explored in "shock and kill" strategies to eliminate the HIV-1 reservoir. For optimal activity against infected targets, NK cells require priming. This study examined how macrophages prime NK cells following HIV-1 infection. We found that HIV-1-infected monocyte-derived macrophages upregulated membrane-bound IL-15Rα, NKG2D ligands, CD48, and IL-18. While crosstalk between NK cells and infected macrophages enhanced proinflammatory cytokine production, it led to only weak priming of NK-cell cytotoxicity. In people living with HIV-1 (PLWH) on antiretroviral therapy, macrophage priming remained intact and polyfunctional, with the strongest response in CD56<sup>dim</sup> KIR+ and/or NKG2A+ NK cells. However, CD56<sup>neg</sup> NK cells -a subset unique to HIV-1 infection- remained dysfunctional. These findings elucidate how HIV-1 alters macrophage-NK cell crosstalk and underscore the need for therapeutic strategies that enhance NK-cell cytotoxicity in efforts toward a functional HIV-1 cure.
Authors
- Glòria Martrus (ORCID: https://orcid.org/0000-0003-2879-3201)
- Frank Kirchhoff (ORCID: https://orcid.org/0000-0002-2324-2761)
- Benedetta Padoan
- Pia Fittje (ORCID: https://orcid.org/0000-0002-0123-9844)
- Julian Schulze zur Wiesch (ORCID: https://orcid.org/0000-0002-5033-1938)
- Sandra Köllmann
- Timo Trenkner (ORCID: https://orcid.org/0000-0001-8276-9398)
- Daniel Sauter (ORCID: https://orcid.org/0000-0001-7665-0040)
- Marcus Altfeld (ORCID: https://orcid.org/0000-0001-5972-2997)
- Christina M. Stürzel
- Wilfredo F. García-Beltrán (ORCID: https://orcid.org/0000-0002-7109-0504)
- Sebastian Schloer (ORCID: https://orcid.org/0000-0002-9944-3017)
- Angelique Hölzemer (ORCID: https://orcid.org/0000-0002-1446-3474)
- Leonore Mensching (ORCID: https://orcid.org/0000-0002-1061-663X)
- Maya Beiersdorfer
- Friederike Reinsberg
- Maher Almahfoud (ORCID: https://orcid.org/0009-0004-9912-7833)
- Annika Zaayenga
Institutions
- Harvard University (US)
- Leibniz Institute of Virology (LIV) (DE)
- Universität Hamburg (DE)
- Universität Ulm (DE)
- Ragon Institute of MGH, MIT and Harvard (US)
- Massachusetts General Hospital (US)
- University Medical Center Hamburg-Eppendorf (DE)
- German Center for Infection Research (DE)
- University of Tübingen (DE)
Publication Details
- Journal
- iScience
- Published
- 2025-06-11
- DOI
- https://doi.org/10.1016/j.isci.2025.112879
- Citations
- 1
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 0.80
Funders
- Deutsches Zentrum für Infektionsforschung
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Hector Stiftung
- European Research Council
- H2020 European Research Council