title: Induction of IL-17 and nonclassical T-cell activation by HIV-Tat protein.
abstract: 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.
authors.affiliation: Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Tory P
authors.initials: TP
authors.lastname: Johnson
authors.forename: Karan
authors.initials: K
authors.lastname: Patel
authors.forename: Kory R
authors.initials: KR
authors.lastname: Johnson
authors.forename: Dragan
authors.initials: D
authors.lastname: Maric
authors.forename: Peter A
authors.initials: PA
authors.lastname: Calabresi
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Hasbun
authors.forename: Avindra
authors.initials: A
authors.lastname: Nath
mesh_terms: D044966:Anti-Retroviral Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015967:Gene Expression Regulation, Viral / Q000276:immunology*; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000209:etiology / Q000276:immunology / Q000503:physiopathology*; D015151:Immunoblotting; D020381:Interleukin-17 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D046228:Microarray Analysis; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D037521:Virulence Factors / Q000134:cerebrospinal fluid / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000134:cerebrospinal fluid / Q000378:metabolism*
chemical_list: D044966:Anti-Retroviral Agents; D020381:Interleukin-17; D037521:Virulence Factors; D054322:tat Gene Products, Human Immunodeficiency Virus
keywords: CNS inflammation; central nervous system; chromatin; chronic inflammation; lymphocyte
references.citation: Nat Med. 2006 Dec;12(12):1365-71
references.pmid: 17115046
references.citation: Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1361-5
references.pmid: 9037058
references.citation: Eur J Immunol. 2010 Jan;40(1):197-203
references.pmid: 19902430
references.citation: PLoS Med. 2010 Dec 21;7(12):e1000384
references.pmid: 21253011
references.citation: Curr Opin Neurol. 2011 Jun;24(3):284-90
references.pmid: 21499099
references.citation: Blood. 2010 Sep 16;116(11):1980-9
references.pmid: 20538805
references.citation: EMBO J. 2010 Apr 21;29(8):1348-62
references.pmid: 20224549
references.citation: Genes Dev. 2005 Mar 1;19(5):542-52
references.pmid: 15706033
references.citation: J Virol. 2005 Feb;79(4):2199-210
references.pmid: 15681422
references.citation: J Immunol. 2010 Jan 15;184(2):545-9
references.pmid: 20008289
references.citation: J Neurovirol. 2000 Apr;6(2):145-55
references.pmid: 10822328
references.citation: Nat Med. 1996 Dec;2(12):1371-5
references.pmid: 8946838
references.citation: J Acquir Immune Defic Syndr. 2008 Apr 15;47(5):544-52
references.pmid: 18362693
references.citation: Neurology. 2006 Aug 8;67(3):383-8
references.pmid: 16894096
references.citation: Crit Rev Immunol. 2009;29(3):219-39
references.pmid: 19538136
references.citation: FEBS Lett. 2010 May 3;584(9):1806-13
references.pmid: 19925791
references.citation: J Control Release. 2012 Jul 20;161(2):582-91
references.pmid: 22516088
references.citation: J Mol Biol. 2011 Jul 29;410(5):997-1007
references.pmid: 21763502
references.citation: J Exp Med. 2005 Jan 17;201(2):233-40
references.pmid: 15657292
references.citation: Acta Neuropathol. 2004 Jul;108(1):17-23
references.pmid: 15085359
references.citation: Biotechnol Prog. 2005 Mar-Apr;21(2):451-9
references.pmid: 15801785
references.citation: AIDS Res Hum Retroviruses. 1996 May 1;12(7):611-9
references.pmid: 8743086
references.citation: J Infect Dis. 2011 Dec 15;204(12):1936-45
references.pmid: 22021620
references.citation: AIDS. 2005 Mar 4;19(4):399-406
references.pmid: 15750393
references.citation: Ann Neurol. 1998 Mar;43(3):340-9
references.pmid: 9506551
references.citation: PLoS One. 2010 Nov 11;5(11):e13540
references.pmid: 21085635
references.citation: Cell Mol Life Sci. 2013 Jul;70(13):2271-90
references.pmid: 23052209
references.citation: Ann Neurol. 1992 Jan;31(1):34-8
references.pmid: 1311910
references.citation: Mol Biol Cell. 2007 Dec;18(12):5014-23
references.pmid: 17928406
references.citation: PLoS One. 2012;7(11):e48702
references.pmid: 23166591
references.citation: Crit Rev Oncol Hematol. 2013 Jul;87(1):80-9
references.pmid: 23317774
references.citation: Mol Biol Cell. 2004 May;15(5):2347-60
references.pmid: 15020715
references.citation: J Virol. 1998 Apr;72(4):3161-8
references.pmid: 9525642
references.citation: Immunity. 2010 Sep 24;33(3):424-36
references.pmid: 20870176
references.citation: Neurochem Int. 2011 May;58(6):656-64
references.pmid: 21315782
references.citation: Top HIV Med. 2009 Sep-Oct;17(4):118-23
references.pmid: 19890183
references.citation: J Infect Dis. 2012 Dec 1;206(11):1715-23
references.pmid: 23002445
references.citation: J Virol. 2007 Apr;81(7):3574-82
references.pmid: 17229711
references.citation: PLoS One. 2012;7(12):e50859
references.pmid: 23227216
references.citation: Cold Spring Harb Perspect Med. 2012 Apr;2(4):a007161
references.pmid: 22474613