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Journal of Virology, August 2001, p. 7543-7554, Vol. 75, No. 16
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.16.7543-7554.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Reactivation of Latent Human Cytomegalovirus in CD14+ Monocytes Is Differentiation Dependent

Cecilia Söderberg-Nauclér,1,2,* Daniel N. Streblow,1 Kenneth N. Fish,1 Justine Allan-Yorke,3 Patricia P. Smith,1 and Jay A. Nelson1,*

Oregon Health Sciences University, Portland, Oregon 972011; Karolinska Institute, Department for Biosciences at Novum, Huddinge, Sweden2; and Institut National de la Santé et de la Recherche Médìcale 395, 31024 Toulouse Cedex, France3

Received 29 January 2001/Accepted 4 May 2001

We have previously demonstrated reactivation of latent human cytomegalovirus (HCMV) in myeloid lineage cells obtained from healthy donors. Virus was obtained from allogenically stimulated monocyte-derived macrophages (Allo-MDM), but not from macrophages differentiated by mitogenic stimulation (ConA-MDM). In the present study, the cellular and cytokine components essential for HCMV replication and reactivation were examined in Allo-MDM. The importance of both CD4+ and CD8+ T cells in the generation of HCMV-permissive Allo-MDM was demonstrated by negative selection or blocking experiments using antibodies directed against both HLA class I and HLA class II molecules. Interestingly, contact of monocytes with CD4 or CD8 T cells was not essential for reactivation of HCMV, since virus was observed in macrophages derived from CD14+ monocytes stimulated by supernatants produced by allogeneic stimulation of peripheral blood mononuclear cells. Examination of the cytokines produced in Allo-MDM and ConA-MDM cultures indicated a significant difference in the kinetics of production and quantity of these factors. Further examination of the cytokines essential for the generation of HCMV-permissive Allo-MDM identified gamma interferon (IFN-gamma ) but not interleukin-1 or -2, tumor necrosis factor alpha, or granulocyte-macrophage colony-stimulating factor as critical components in the generation of these macrophages. In addition, although IFN-gamma was crucial for reactivation of latent HCMV, addition of IFN-gamma to unstimulated macrophage cultures was insufficient to reactivate virus. Thus, this study characterizes two distinct monocyte-derived cell types which can be distinguished by their ability to reactivate and support HCMV replication and identifies the critical importance of IFN-gamma in the reactivation of HCMV.

* Corresponding author. Mailing address for Jay A. Nelson: Dept of Microbiology and Immunology, Oregon Health Sciences University, Portland, OR 97201-3098. Phone: (503) 494-7769. Fax: (503) 494-2441. E-mail: nelsonj{at}ohsu.edu. Mailing address for Cecilia Söderberg-Nauclér: Karolinska Institute, Department for Biosciences at Novum, S-141 57 Huddinge, Sweden. Phone: 46 8 608 9118. Fax: 46 8 774 5538. E-mail: cecilia.soderberg-naucler{at}cbt.ki.se.

Journal of Virology, August 2001, p. 7543-7554, Vol. 75, No. 16
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.16.7543-7554.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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