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Journal of Virology, November 2007, p. 11593-11603, Vol. 81, No. 21
0022-538X/07/$08.00+0     doi:10.1128/JVI.00760-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Regulatory T-Cell Markers, Indoleamine 2,3-Dioxygenase, and Virus Levels in Spleen and Gut during Progressive Simian Immunodeficiency Virus Infection{triangledown}

Adriano Boasso,1* Monica Vaccari,2 Anna Hryniewicz,2,3 Dietmar Fuchs,4 Janos Nacsa,2 Valentina Cecchinato,2 Jan Andersson,5 Genoveffa Franchini,2 Gene M. Shearer,1 and Claire Chougnet6

Experimental Immunology Branch, CCR, National Cancer Institute, National Institutes of Health, Bethesda, Maryland,1 Animal Models and Retroviral Vaccines Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland,2 Department of General and Experimental Pathology, Medical University of Bialystok Mickiewicza 2c, 15-222 Bialystok, Poland,3 Division of Biological Chemistry Biocentre, Innsbruck Medical University, Ludwig Boltzmann Institute of AIDS-Research, Innsbruck, Austria,4 Center for Infectious Medicine, Division of Infectious Diseases, Karolinska Institute, Karolinska University Hospital, 141 86 Stockholm, Sweden,5 Division of Molecular Immunology, Cincinnati Children's Hospital Research Foundation and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio6

Received 9 April 2007/ Accepted 8 August 2007

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 (Treg), 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 (SIVHI) compared to animals with low viremia (SIVLO). 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 SIVHI, further challenging the classical definition of Treg as CD4+ CD25+ T cells. Similar to CTLA-4 and FoxP3, expression of indoleamine 2,3-dioxygenase (IDO), an immunosuppressive enzyme induced by Treg in antigen-presenting cells, was increased in the spleens, mesenteric LN, colons, and jejuna from SIVHI compared to SIVLO and directly correlated to SIV RNA in the same tissues. Accordingly, plasma kynurenine/tryptophan, a marker for IDO enzymatic activity, was significantly higher in SIVHI compared to SIVLO and correlated with plasma viral levels. Increased Treg 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.

* Corresponding author. Mailing address: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, 10 Center Dr., Bldg. 10, Rm. 4B36, Bethesda, MD 20892. Phone: (301) 435-6420. Fax: (301) 402-3643. E-mail: boassoa{at}mail.nih.gov

{triangledown} Published ahead of print on 22 August 2007.

Journal of Virology, November 2007, p. 11593-11603, Vol. 81, No. 21
0022-538X/07/$08.00+0     doi:10.1128/JVI.00760-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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