Harnessing NK cell immune functions for immunotherapeutic interventions in HIV-1 infection Christian Körner, Ph.D. Research Department Virus Immunology Heinrich Pette Institute Leibniz Institute for Experimental Virology AREVIR-Meeting – 3.05.2019 1
NK cells in viral infections 2
NK cell deficiencies 3 3 Orange, Microbes and Infection (2002)
NK cells in natural HIV-1 infection Fraction of AIDS-free individuals Martin et al., Nature Genetics ( 2002) HLA-Bw4-Iso80 KIR3DS1 time since seroconversion (y) Martin et al., Nature Genetics (2007) KIR3DL1 HLA-Bw4 4
HIV-1 immune evasion Alter et al. Nature , 2011 Hölzemer/Thobakgale et al., PLoS Medicine (2015) Description of KIR -associated amino acid polymorphisms in HIV-1 infected individuals. • HIV-1 selects variants to evade NK-cell-mediated immune pressure. • NK-cell-mediated control of HIV-1 seems to be genetically hard-wired (KIR/HLA-I). • In principle, NK cells have the ability to control HIV-1 infection. • 5
How can we utilize NK cell functions to control HIV-1 infection? 6
How do NK cells work? 7 Adapted from Vivier et al., Nature Reviews Immunology (2012)
NK cell functions Anti-viral activity Shaping adaptive immune Tumor surveillance responses DC Killing of immature DC Cytotoxicity (“DC-editing”) (granzymes, perforin) NK T Differentiation (IFN-y) ADCC cell cell T IFN-y, TNF-a, Elimination of T cells cell MIP-1 α , MIP-1 β 8
NK cell functions Anti-viral activity Tumor surveillance Cytotoxicity (granzymes, perforin) NK ADCC cell IFN-y, TNF-a, MIP-1 γ , MIP-1 β 9
Antibodies Inducing „missing self“ Inducing ADCC using bNAbs KIR Y _ NK IPH2102 CD16 Y cell + Y _ Monalizumab NKG2A ClinicalTrial.gov ID numbers: NCT02399917, ClinicalTrials.gov ID: NCT02018510 NCT02599649, NCT02252263, NCT02481297, NCT01687387, NCT01714739, NCT01592370, NCT01750580. Trials.gov ID numbers: NCT02921685, NCT02643550 10
Enhancing NK cell functions ClinicalTrials.gov ID: NCT02077868, ClinicalTrials.gov ID: NCT01885897 NCT02200081 and NCT02668770 11 Adapted from Ram et al., JLB (2019)
Addressing the mammoth in the room 12 Gary Larson
NK cell memory 13 Paust, Blish, Reeves, JV (2017)
Summary NK cells are promising target for immunotherapies. • Enhancement of NK cell-mediated antiviral functions can be achieved by … • 1. Blockade of inhibitory receptors to induce “missing-self” 2. Induction of ADCC using bNAbs (“combined arms”) 3. Stimulation of NK cells through cytokines 4. Eliciting “memory-like” NK cells responses through vaccination 5. CAR NK cells 14
Thank for you attention Research Department Virus Immunology Heinrich Pette Institute Leibniz Institute for Experimental Virology 15
Acknowledgements Leidos Biomedical Research Inc. Frederick National Laboratory for Cancer Research Mary Carrington Pat Martin University Medical Hospital Hamburg- Eppendorf Julian Schulze zur Wiesch University Medical Hospital Bonn Jacob Nattermann Jürgen Rockstroh Institute of Molecular Virology, Univerity Hospital of Ulm Frank Kirchhoff Daniel Sauter Institute for Transfusion medicine 16
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