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* Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, Zurich, Switzerland;
Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland;
Millennium Pharmaceuticals, Cambridge, MA 02139;
Tibotec, Mechelen, Belgium;
¶ Institute of Clinical Immunology, University Hospital of Zurich, Zurich, Switzerland; and
|| Department of Pharmacology, University of Berne, Berne, Switzerland
To gain insights into the molecular mechanisms underlying early host responses to HIV in the CD4+ T cell target population, we examined gene expression in CD4+ T cells isolated 24 h after ex vivo HIV infection of lymphocyte aggregate cultures derived from human tonsils. Gene profiling showed a distinct up-regulation of genes related to immune response and response to virus, notably of IFN-stimulated genes (ISGs), irrespective of the coreceptor tropism of the virus. This mostly IFN-
-dependent gene signature suggested the involvement of plasmacytoid dendritic cells, a principal component of the antiviral immune response. Indeed, depletion of plasmacytoid dendritic cells before HIV inoculation abrogated transcriptional up-regulation of several ISGs and resulted in increased levels of HIV replication. Treatment with a blocking anti-IFN-R Ab yielded increased HIV replication; conversely, HIV replication was decreased in pDC-depleted cultures treated with IFN-. Among up-regulated ISGs was also TRAIL, indicating a potential role of the IFN signature in apoptosis. However, a blocking anti-TRAIL Ab did not abrogate apoptosis of CD4+ T cells in CXCR4-tropic HIV-infected cultures, suggesting the involvement of pathways other than TRAIL mediated. We conclude that acute HIV infection of lymphoid tissue results in up-regulation of ISGs in CD4+ T cells, which induces an anti-HIV state but not apoptosis.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 A.A. and M.U. contributed equally to this work.
2 Current address: Antigen Express, 100 Barber Avenue, Worcester, MA 01606.
3 Address correspondence and reprint requests to Dr. Roberto F. Speck, Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, Raemistrasse 100, 8091 Zurich, Switzerland. E-mail address: roberto.speck{at}usz.ch
4 Abbreviations used in this paper: R5, CCR5-using; DC, dendritic cell; pDC, plasmacytoid DC; ISG, IFN-stimulated gene; HLAC, human lymphoid aggregate culture; p.i., postinfection; CI, confidence interval; IRF, IFN regulatory factor; X4, CXCR4-using; OAS, 2'-5'-oligoadenylate synthetase; sTRAIL, soluble TRAIL.
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