Journal Article

Induction of IL-17 and nonclassical T-cell activation by HIV-Tat protein

Maric, Dragan, Johnson, Tory P., Patel, Karan, Marie, Dragan, Hasbun, Rodrigo, Nath, Avindra, Johnson, Kory R., Calabresi, Peter A.

2013

Overview

Chronic immune activation is a major complication of antiretroviral therapy (ART) for HIV infection and can cause a devastating immune reconstitution inflammatory syndrome (IRIS) in the brain. The mechanism of T-cell activation in this population is not well understood. We found HIV-Tat protein and IL-17–expressing mononuclear cells in the brain of an individual with IRIS. Tat was also present in the CSF of individuals virologically controlled on ART. Hence we examined if Tat protein could directly activate T cells. Tat transcriptionally dysregulated 94 genes and induced secretion of 11 cytokines particularly activation of IL-17 signaling pathways supporting the development of a proinflammatory state. Tat increased IL-17 transcription and secretion in T cells. Tat entered the T cells rapidly by clathrin-mediated endocytosis and localized to both the cytoplasm and the nucleus. Tat activated T cells through a nonclassical pathway dependent upon vascular endothelial growth factor receptor-2 and downstream secondary signaling pathways but independent of the T-cell receptor. However, Tat stimulation of T cells did not induce T-cell proliferation but increased viral infectivity. This study demonstrates Tat’s role as a virulence factor, by driving T-cell activation and contributing to IRIS pathophysiology. This supports the necessity of an anti-Tat therapy in conjunction with ART and identifies multiple targetable pathways to prevent Tat-mediated T-cell activation.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Anti-Retroviral Agents - adverse effects / Anti-Retroviral Agents - therapeutic use / Antiretroviral agents / Antiretroviral drugs / Biological Sciences / brain / Brain - metabolism / Cell lines / Central nervous system / Chromatin / cytoplasm / Drug therapy / endocytosis / Enzyme-Linked Immunosorbent Assay / Flow Cytometry / Gene Expression Regulation, Viral - immunology / genes / Histones / HIV / HIV 1 / HIV infections / HIV Infections - drug therapy / Human immunodeficiency virus / Humans / Immune Reconstitution Inflammatory Syndrome - etiology / Immune Reconstitution Inflammatory Syndrome - immunology / Immune Reconstitution Inflammatory Syndrome - physiopathology / Immunoblotting / Infections / Inflammation / Inflammatory diseases / interleukin-17 / Interleukin-17 - metabolism / Leukocytes, Mononuclear - metabolism / Lymphocyte Activation - immunology / Lymphocytes / Microarray Analysis / pathophysiology / Proteins / secretion / signal transduction / Signal Transduction - immunology / T lymphocytes / T-Lymphocytes - immunology / tat Gene Products, Human Immunodeficiency Virus - cerebrospinal fluid / tat Gene Products, Human Immunodeficiency Virus - metabolism / therapeutics / transcription (genetics) / vascular endothelial growth factor receptor-2 / virulence / Virulence Factors - cerebrospinal fluid / Virulence Factors - metabolism