PMID- 23898208 OWN - NLM STAT- MEDLINE DCOM- 20131111 LR - 20220418 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 110 IP - 33 DP - 2013 Aug 13 TI - Induction of IL-17 and nonclassical T-cell activation by HIV-Tat protein. PG - 13588-93 LID - 10.1073/pnas.1308673110 [doi] AB - 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. FAU - Johnson, Tory P AU - Johnson TP AD - Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. FAU - Patel, Karan AU - Patel K FAU - Johnson, Kory R AU - Johnson KR FAU - Maric, Dragan AU - Maric D FAU - Calabresi, Peter A AU - Calabresi PA FAU - Hasbun, Rodrigo AU - Hasbun R FAU - Nath, Avindra AU - Nath A LA - eng SI - GEO/GSE44460 GR - R01 NS039253/NS/NINDS NIH HHS/United States GR - F31 NS063855/NS/NINDS NIH HHS/United States GR - ImNIH/Intramural NIH HHS/United States GR - R01 NS056884/NS/NINDS NIH HHS/United States GR - R01NS056884/NS/NINDS NIH HHS/United States GR - F31NS063855/NS/NINDS NIH HHS/United States GR - R01NS039253/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural DEP - 20130729 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Anti-Retroviral Agents) RN - 0 (Interleukin-17) RN - 0 (Virulence Factors) RN - 0 (tat Gene Products, Human Immunodeficiency Virus) SB - IM MH - Anti-Retroviral Agents/*adverse effects/therapeutic use MH - Brain/metabolism MH - Enzyme-Linked Immunosorbent Assay MH - Flow Cytometry MH - Gene Expression Regulation, Viral/*immunology MH - HIV Infections/*drug therapy MH - Humans MH - Immune Reconstitution Inflammatory Syndrome/etiology/immunology/*physiopathology MH - Immunoblotting MH - Interleukin-17/metabolism MH - Leukocytes, Mononuclear/metabolism MH - Lymphocyte Activation/immunology MH - Microarray Analysis MH - Signal Transduction/*immunology MH - T-Lymphocytes/immunology MH - Virulence Factors/cerebrospinal fluid/*metabolism MH - tat Gene Products, Human Immunodeficiency Virus/cerebrospinal fluid/*metabolism PMC - PMC3746932 OTO - NOTNLM OT - CNS inflammation OT - central nervous system OT - chromatin OT - chronic inflammation OT - lymphocyte COIS- The authors declare no conflict of interest. EDAT- 2013/07/31 06:00 MHDA- 2013/11/12 06:00 PMCR- 2014/02/13 CRDT- 2013/07/31 06:00 PHST- 2013/07/31 06:00 [entrez] PHST- 2013/07/31 06:00 [pubmed] PHST- 2013/11/12 06:00 [medline] PHST- 2014/02/13 00:00 [pmc-release] AID - 1308673110 [pii] AID - 201308673 [pii] AID - 10.1073/pnas.1308673110 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13588-93. doi: 10.1073/pnas.1308673110. Epub 2013 Jul 29.