Defining the Effects of PKC Modulator HIV Latency-Reversing Agents on Natural Killer Cells

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Published: Apr 24, 2024
DOI: https://doi.org/10.20411/pai.v9i1.673
Keywords:
Killer Cells, Natural, Protein Kinase C, HIV-1, Virus Latency, Immunity, Acquired Immunodeficiency Syndrome

Main Article Content

Melanie Dimapasoc
Molecular Biology Institute, University of California Los Angeles; Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, California
https://orcid.org/0000-0003-0328-315X
Jose A. Moran
Department of Microbiology and Molecular Genetics, School of Medicine, University of California Irvine, California
https://orcid.org/0000-0002-7537-6307
Steve W. Cole
UCLA Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California
https://orcid.org/0000-0001-6319-2829
Alok Ranjan
Department of Chemistry, Stanford University, Stanford, California
Rami Hourani
Department of Chemistry, Stanford University, Stanford, California
Jocelyn T. Kim
Department of Medicine, Division of Infectious Diseases, University of California Los Angeles, Los Angeles, California
https://orcid.org/0000-0001-7040-5773
Paul A. Wender
Department of Chemistry, Stanford University; Department of Chemical and Systems Biology, Stanford University, Stanford, California
https://orcid.org/0000-0001-6319-2829
Matthew D. Marsden
Department of Microbiology and Molecular Genetics, School of Medicine, University of California Irvine; Department of Medicine, Division of Infectious Diseases, School of Medicine, University of California, Irvine, Irvine, California
https://orcid.org/0000-0002-4857-8712
Jerome A. Zack
Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles; Department of Medicine, Division of Hematology and Oncology, University of California Los Angeles, Los Angeles, Californi
https://orcid.org/0000-0001-5486-8495

Abstract

Background: Latency reversing agents (LRAs) such as protein kinase C (PKC) modulators can reduce rebound-competent HIV reservoirs in small animal models. Furthermore, administration of natural killer (NK) cells following LRA treatment improves this reservoir reduction. It is currently unknown why the combination of a PKC modulator and NK cells is so potent and whether exposure to PKC modulators may augment NK cell function in some way.


Methods: Primary human NK cells were treated with PKC modulators (bryostatin-1, prostratin, or the designed, synthetic bryostatin-1 analog SUW133), and evaluated by examining expression of activation markers by flow cytometry, analyzing transcriptomic profiles by RNA sequencing, measuring cytotoxicity by co-culturing with K562 cells, assessing cytokine production by Luminex assay, and examining the ability of cytokines and secreted factors to independently reverse HIV latency by co-culturing with Jurkat-Latency (J-Lat) cells.


Results: PKC modulators increased expression of proteins involved in NK cell activation. Transcriptomic profiles from PKC-treated NK cells displayed signatures of cellular activation and enrichment of genes associated with the NFκB pathway. NK cell cytotoxicity was unaffected by prostratin but significantly decreased by bryostatin-1 and SUW133. Cytokines from PKC-stimulated NK cells did not induce latency reversal in J-Lat cell lines. 


Conclusions: Although PKC modulators have some significant effects on NK cells, their contribution in “kick and kill” strategies is likely due to upregulating HIV expression in CD4+ T cells, not directly enhancing the effector functions of NK cells. This suggests that PKC modulators are primarily augmenting the “kick” rather than the “kill” arm of this HIV cure approach.

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