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Journal of Virology, October 2009, p. 10664-10676, Vol. 83, No. 20
0022-538X/09/$08.00+0     doi:10.1128/JVI.02584-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Mucosal Innate and Adaptive Immune Responses against Herpes Simplex Virus Type 2 in a Humanized Mouse Model{triangledown}

Amanda Kwant-Mitchell, Ali A. Ashkar,{dagger} and Kenneth L. Rosenthal{dagger}*

Michael G. DeGroote Institute for Infectious Disease Research, Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada L8N 3Z5

Received 15 December 2008/ Accepted 24 July 2009

Genital herpes, caused by herpes simplex virus type 2 (HSV-2), is one of the most prevalent sexually transmitted diseases worldwide and a risk factor for acquiring human immunodeficiency virus. Although many vaccine candidates have shown promising results in animal models, they have failed to be effective in human trials. In this study, a humanized mouse strain was evaluated as a potential preclinical model for studying human immune responses to HSV-2 infection and vaccination. Immunodeficient mouse strains were examined for their abilities to develop human innate and adaptive immune cells after transplantation of human umbilical cord stem cells. A RAG2–/– {gamma}c–/– mouse strain with a BALB/c background was chosen as the most appropriate model and was then examined for its ability to mount innate and adaptive immune responses to intravaginal HSV-2 infection and immunization. After primary infection, human cells in the lymph nodes were able to generate a protective innate immune response and produce gamma interferon (IFN-{gamma}). After intravaginal immunization and infection, human T cells and NK cells were found in the genital tract and iliac lymph nodes. In addition, human T cells in the spleen, lymph nodes, and vaginal tract were able to respond to stimulation with HSV-2 antigens by replicating and producing IFN-{gamma}. Human B cells were also able to produce HSV-2-specific immunoglobulin G. These adaptive responses were also shown to be protective and reduce local viral replication in the genital tract. This approach provides a means for studying human immune responses in vivo using a small-animal model and may become an important preclinical tool.

* Corresponding author. Mailing address: Department of Pathology & Molecular Medicine, McMaster University, MDCL 4019, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5. Phone: (905) 525-9140, ext. 22375. Fax: (905) 522-6750. E-mail: rosenthl{at}mcmaster.ca

{triangledown} Published ahead of print on 5 August 2009.

{dagger} A.A.A. and K.L.R. contributed equally to this work.

Journal of Virology, October 2009, p. 10664-10676, Vol. 83, No. 20
0022-538X/09/$08.00+0     doi:10.1128/JVI.02584-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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