Immune Checkpoint Blockade Restores HIV-Specific CD4 T Cell Help for NK Cells

• Published in: The Journal of immunology (1950) Vol. 201; no. 3; pp. 971 - 981
• Main Authors: Porichis, Filippos, Hart, Meghan G, Massa, Alexandra, Everett, Holly L, Morou, Antigoni, Richard, Jonathan, Brassard, Nathalie, Veillette, Maxime, Hassan, Muska, Ly, Ngoc Le, Routy, Jean-Pierre, Freeman, Gordon J, Dubé, Mathieu, Finzi, Andrés, Kaufmann, Daniel E
• Format: Journal Article
• Language: English
• Published: United States American Association of Immunologists 01.08.2018
• Subjects: Adaptive immunity; Anti-Retroviral Agents - pharmacology; Antiretroviral therapy; Cancer; CD4 antigen; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Cohort Studies; Cytokines; Degranulation; HIV; HIV Infections - drug therapy; HIV Infections - immunology; HIV-1 - drug effects; HIV-1 - immunology; Human immunodeficiency virus; Humans; Immune checkpoint; Immunomodulation; Infections; Innate immunity; Interferon-gamma - immunology; Interleukin 10; Interleukin 12; Interleukin 2; Interleukin-10 - immunology; Interleukin-2 - immunology; K562 Cells; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - virology; Lymphocytes; Lymphocytes T; Natural killer cells; PD-1 protein; Peripheral blood mononuclear cells; Programmed Cell Death 1 Receptor - immunology; Viral Load - drug effects; Viral Load - immunology; Viremia; γ-Interferon
• DOI: 10.4049/jimmunol.1701551
• ISSN: 0022-1767; 1550-6606

Immune exhaustion is an important feature of chronic infections, such as HIV, and a barrier to effective immunity against cancer. This dysfunction is in part controlled by inhibitory immune checkpoints. Blockade of the PD-1 or IL-10 pathways can reinvigorate HIV-specific CD4 T cell function in vitro, as measured by cytokine secretion and proliferative responses upon Ag stimulation. However, whether this restoration of HIV-specific CD4 T cells can improve help to other cell subsets impaired in HIV infection remains to be determined. In this study, we examine a cohort of chronically infected subjects prior to initiation of antiretroviral therapy (ART) and individuals with suppressed viral load on ART. We show that IFN-γ induction in NK cells upon PBMC stimulation by HIV Ag varies inversely with viremia and depends on HIV-specific CD4 T cell help. We demonstrate in both untreated and ART-suppressed individuals that dual PD-1 and IL-10 blockade enhances cytokine secretion of NK cells via restored HIV-specific CD4 T cell function, that soluble factors contribute to these immunotherapeutic effects, and that they depend on IL-2 and IL-12 signaling. Importantly, we show that inhibition of the PD-1 and IL-10 pathways also increases NK degranulation and killing of target cells. This study demonstrates a previously underappreciated relationship between CD4 T cell impairment and NK cell exhaustion in HIV infection, provides a proof of principle that reversal of adaptive immunity exhaustion can improve the innate immune response, and suggests that immune checkpoint modulation that improves CD4/NK cell cooperation can be used as adjuvant therapy in HIV infection.