HIV-1 infection of macrophages differentially primes NK-cell cytotoxicity and proinflammatory cytokine production

Leonore Mensching; Maya Beiersdorfer; Sebastian Schloer; Sandra Köllmann; Friederike Reinsberg; Benedetta Padoan; Pia Fittje; Timo Trenkner; Annika Zaayenga; Gloria Martrus; Maher Almahfoud; Christina M Stürzel; Daniel Sauter; Frank Kirchhoff; Julian Schulze Zur Wiesch; Marcus Altfeld; Wilfredo F Garcia-Beltran; Angelique Hoelzemer

doi:10.1016/j.isci.2025.112879

HIV-1 infection of macrophages differentially primes NK-cell cytotoxicity and proinflammatory cytokine production

iScience. 2025 Jun 11;28(7):112879. doi: 10.1016/j.isci.2025.112879. eCollection 2025 Jul 18.

Authors

Leonore Mensching^{1

2}, Maya Beiersdorfer¹, Sebastian Schloer³, Sandra Köllmann^{1

2}, Friederike Reinsberg^{1

2

4}, Benedetta Padoan², Pia Fittje², Timo Trenkner¹, Annika Zaayenga¹, Gloria Martrus², Maher Almahfoud¹, Christina M Stürzel⁵, Daniel Sauter⁶, Frank Kirchhoff⁵, Julian Schulze Zur Wiesch^{1

4}, Marcus Altfeld², Wilfredo F Garcia-Beltran^{7

8}, Angelique Hoelzemer^{1

2

4

9}

Affiliations

¹ Department of Medicine, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
² Research Department of Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.
³ Institute of Immunology, Research Group Immunopharmacology, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
⁴ German Center for Infection Research (DZIF), Site Hamburg-Lübeck-Borstel-Riems, Borstel, Germany.
⁵ Institute of Molecular Virology, University Medical Center, Ulm, Germany.
⁶ Institute for Medical Virology and Epidemiology of Viral Diseases, Eberhard Karls University Tübingen, Tübingen, Germany.
⁷ Ragon Institute of Massachusetts General Hospital, MIT and Harvard, Cambridge, MA, USA.
⁸ Department of Pathology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
⁹ Institute for Infection and Vaccine Development (IIRVD), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.

Abstract

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^dim KIR+ and/or NKG2A+ NK cells. However, CD56^neg 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.

Keywords: Immune response; Immunology; Virology.