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Journal of Virology, July 2009, p. 7305-7321, Vol. 83, No. 14
0022-538X/09/$08.00+0     doi:10.1128/JVI.02207-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Induction of Robust Cellular and Humoral Virus-Specific Adaptive Immune Responses in Human Immunodeficiency Virus-Infected Humanized BLT Mice{triangledown}

Diana M. Brainard,1,2 Edward Seung,1 Nicole Frahm,2,3 Annaiah Cariappa,4 Charles C. Bailey,5 William K. Hart,1 Hae-Sook Shin,1 Sarah F. Brooks,1 Heather L. Knight,2 Quentin Eichbaum,2 Yong-Guang Yang,6 Megan Sykes,6 Bruce D. Walker,2 Gordon J. Freeman,7 Shiv Pillai,4 Susan V. Westmoreland,5 Christian Brander,2,8,9 Andrew D. Luster,1,{dagger}* and Andrew M. Tager1,{dagger}*

Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129,1 Ragon Institute of MGH, MIT, and Harvard and Division of AIDS, Harvard Medical School, Charlestown, Massachusetts 02129,2 Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109,3 Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129,4 Division of Comparative Pathology, New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772,5 Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129,6 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115,7 Institucio Catalana de Recerca i Estudis Avancats, Barcelona, Spain,8 Irsicaixa Foundation, Badalona, Spain9

Received 17 October 2008/ Accepted 22 April 2009

The generation of humanized BLT mice by the cotransplantation of human fetal thymus and liver tissues and CD34+ fetal liver cells into nonobese diabetic/severe combined immunodeficiency mice allows for the long-term reconstitution of a functional human immune system, with human T cells, B cells, dendritic cells, and monocytes/macrophages repopulating mouse tissues. Here, we show that humanized BLT mice sustained high-level disseminated human immunodeficiency virus (HIV) infection, resulting in CD4+ T-cell depletion and generalized immune activation. Following infection, HIV-specific humoral responses were present in all mice by 3 months, and HIV-specific CD4+ and CD8+ T-cell responses were detected in the majority of mice tested after 9 weeks of infection. Despite robust HIV-specific responses, however, viral loads remained elevated in infected BLT mice, raising the possibility that these responses are dysfunctional. The increased T-cell expression of the negative costimulator PD-1 recently has been postulated to contribute to T-cell dysfunction in chronic HIV infection. As seen in human infection, both CD4+ and CD8+ T cells demonstrated increased PD-1 expression in HIV-infected BLT mice, and PD-1 levels in these cells correlated positively with viral load and inversely with CD4+ cell levels. The ability of humanized BLT mice to generate both cellular and humoral immune responses to HIV will allow the further investigation of human HIV-specific immune responses in vivo and suggests that these mice are able to provide a platform to assess candidate HIV vaccines and other immunotherapeutic strategies.

* Corresponding author. Mailing address: Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Building 149-8301, 149 13th St., Charlestown, MA 02129. Phone: (617) 724-7368. Fax: (617) 726-5651. E-mail for A. M. Tager: amtager{at}partners.org. E-mail for A. D. Luster: aluster{at}mgh.harvard.edu

{triangledown} Published ahead of print on 6 May 2009.

{dagger} These authors contributed equally.

Journal of Virology, July 2009, p. 7305-7321, Vol. 83, No. 14
0022-538X/09/$08.00+0     doi:10.1128/JVI.02207-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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