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Journal of Virology, April 2007, p. 3477-3486, Vol. 81, No. 7
0022-538X/07/$08.00+0     doi:10.1128/JVI.01552-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Distinct Transcriptional Profiles in Ex Vivo CD4⁺ and CD8⁺ T Cells Are Established Early in Human Immunodeficiency Virus Type 1 Infection and Are Characterized by a Chronic Interferon Response as Well as Extensive Transcriptional Changes in CD8⁺ T Cells ^,

Martin D. Hyrcza,¹ Colin Kovacs,² Mona Loutfy,² Roberta Halpenny,² Lawrence Heisler,¹ Stuart Yang,¹ Olivia Wilkins,¹ Mario Ostrowski,^3* and Sandy D. Der¹

Department of Laboratory Medicine and Pathobiology, University of Toronto,¹ Canadian Immunodeficiency Research Collaborative,² Departments of Immunology and Clinical Sciences Division and St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada³

Received 19 July 2006/ Accepted 16 January 2007

Changes in T-cell function are a hallmark of human immunodeficiency virus type 1 (HIV-1) infection, but the pathogenic mechanisms leading to these changes are unclear. We examined the gene expression profiles in ex vivo human CD4⁺ and CD8⁺ T cells from untreated HIV-1-infected individuals at different clinical stages and rates of disease progression. Profiles of pure CD4⁺ and CD8⁺ T-cell subsets from HIV-1-infected nonprogressors with controlled viremia were indistinguishable from those of individuals not infected with HIV-1. Similarly, no gene clusters could distinguish T cells from individuals with early infection from those seen in chronic progressive HIV-1 infection, whereas differences were observed between uninfected individuals or nonprogressors versus early or chronic progressors. In early and chronic HIV-1 infection, three characteristic gene expression signatures were observed. (i) CD4⁺ and CD8⁺ T cells showed increased expression of interferon-stimulated genes (ISGs). However, some ISGs, including CXCL9, CXCL10, and CXCL11, and the interleukin-15 alpha receptor were not upregulated. (ii) CD4⁺ and CD8⁺ T cells showed a cluster similar to that observed in thymocytes. (iii) More genes were differentially regulated in CD8⁺ T cells than in CD4⁺ T cells, including a cluster of genes downregulated exclusively in CD8⁺ T cells. In conclusion, HIV-1 infection induces a persistent T-cell transcriptional profile, early in infection, characterized by a dramatic but potentially aberrant interferon response and a profile suggesting an active thymic output. These findings highlight the complexity of the host-virus relationship in HIV-1 infection.

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* Corresponding author. Mailing address: Clinical Sciences Division, University of Toronto, Medical Sciences Building, Rm. 6271, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada. Phone: 416.946.5805. Fax: 416.978.8765. E-mail: m.ostrowski{at}utoronto.ca.

Published ahead of print on 24 January 2007.

Supplemental material for this article may be found at http://jvi.asm.org/.

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Journal of Virology, April 2007, p. 3477-3486, Vol. 81, No. 7
0022-538X/07/$08.00+0     doi:10.1128/JVI.01552-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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