Regulatory T-cell markers, indoleamine 2,3-dioxygenase, and virus levels in spleen and gut during progressive simian immunodeficiency virus infection.
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.
Boasso
Adriano
A
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA. boassoa@mail.nih.gov
Vaccari
Monica
M
Hryniewicz
Anna
A
Fuchs
Dietmar
D
Nacsa
Janos
J
Cecchinato
Valentina
V
Andersson
Jan
J
Franchini
Genoveffa
G
Shearer
Gene M
GM
Chougnet
Claire
C
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000943:Antigens, Differentiation / Q000096:biosynthesis; D060908:CTLA-4 Antigen; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D015971:Gene Expression Regulation, Enzymologic; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis* / Q000737:chemistry; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D007422:Intestines / Q000201:enzymology / Q000821:virology*; D007737:Kynurenine / Q000097:blood; D008253:Macaca mulatta; D016097:Simian Acquired Immunodeficiency Syndrome / Q000201:enzymology / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000378:metabolism*; D013154:Spleen / Q000201:enzymology / Q000821:virology*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D014364:Tryptophan / Q000097:blood; D014779:Virus Replication
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D051858:Forkhead Transcription Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D053645:Interleukin-2 Receptor alpha Subunit; D007737:Kynurenine; D014364:Tryptophan
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