Regulatory T-cell markers, indoleamine 2,3-dioxygenase, and virus levels in spleen and gut during progressive simian immunodeficiency virus infection

J Virol. 2007 Nov;81(21):11593-603. doi: 10.1128/JVI.00760-07. Epub 2007 Aug 22.

Abstract

High levels of viral replication occur in gut-associated lymphoid tissue (GALT) and other lymphoid tissues (LT) since the early phase of human/simian immunodeficiency virus (HIV/SIV) infection. Regulatory T cells (T(reg)), a subset of immunosuppressive T cells expressing CTLA-4 and the FoxP3 transcription factor, accumulate in LT during HIV/SIV infection. Here we show that FoxP3 and CTLA-4 mRNA are increased in leukocytes from the spleens, lymph nodes (LN), and mucosal sites of chronically SIV-infected macaques with high viremia (SIV(HI)) compared to animals with low viremia (SIV(LO)). FoxP3 and CTLA-4 correlated with SIV RNA levels in tissues; SIV virus levels in the spleen, inguinal LN, mesenteric LN, colon, and jejunum directly correlated with the plasma virus level. Importantly, CTLA-4 and FoxP3 mRNA were predominantly increased in the CD25(-) subpopulation of leukocytes from SIV(HI), further challenging the classical definition of T(reg) as CD4(+) CD25(+) T cells. Similar to CTLA-4 and FoxP3, expression of indoleamine 2,3-dioxygenase (IDO), an immunosuppressive enzyme induced by T(reg) in antigen-presenting cells, was increased in the spleens, mesenteric LN, colons, and jejuna from SIV(HI) compared to SIV(LO) and directly correlated to SIV RNA in the same tissues. Accordingly, plasma kynurenine/tryptophan, a marker for IDO enzymatic activity, was significantly higher in SIV(HI) compared to SIV(LO) and correlated with plasma viral levels. Increased T(reg) and IDO in LT of SIV-infected macaques may be the consequence of increased tissue inflammation and/or may favor virus replication during the chronic phase of SIV infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / biosynthesis
  • Antigens, Differentiation / biosynthesis
  • CTLA-4 Antigen
  • Forkhead Transcription Factors / biosynthesis
  • Gene Expression Regulation, Enzymologic
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / biosynthesis*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / chemistry
  • Interleukin-2 Receptor alpha Subunit / biosynthesis
  • Intestines / enzymology
  • Intestines / virology*
  • Kynurenine / blood
  • Macaca mulatta
  • Simian Acquired Immunodeficiency Syndrome / enzymology
  • Simian Acquired Immunodeficiency Syndrome / virology*
  • Simian Immunodeficiency Virus / metabolism*
  • Spleen / enzymology
  • Spleen / virology*
  • T-Lymphocytes, Regulatory / metabolism*
  • Tryptophan / blood
  • Virus Replication

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Forkhead Transcription Factors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Interleukin-2 Receptor alpha Subunit
  • Kynurenine
  • Tryptophan