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Journal of Virology, February 2006, p. 1850-1862, Vol. 80, No. 4
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.4.1850-1862.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

CD4-Specific Transgenic Expression of Human Cyclin T1 Markedly Increases Human Immunodeficiency Virus Type 1 (HIV-1) Production by CD4+ T Lymphocytes and Myeloid Cells in Mice Transgenic for a Provirus Encoding a Monocyte-Tropic HIV-1 Isolate

Jinglin Sun,1,{dagger} Timothy Soos,2,3,{dagger} Vineet N. KewalRamani,2,3 Kristin Osiecki,1 Jian Hua Zheng,1 Laurie Falkin,1 Laura Santambrogio,4 Dan R. Littman,2,3 and Harris Goldstein1,5*

Departments of Microbiology & Immunology,1 Pathology,4 Pediatrics, Albert Einstein College of Medicine, Bronx, New York 10461,5 Molecular Pathogenesis Program,2 The Howard Hughes Medical Institute, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 100163

Received 24 August 2005/ Accepted 30 November 2005

Human immunodeficiency virus type 1 (HIV-1)-encoded Tat provides transcriptional activation critical for efficient HIV-1 replication by interacting with cyclin T1 and recruiting P-TEFb to efficiently elongate the nascent HIV transcript. Tat-mediated transcriptional activation in mice is precluded by species-specific structural differences that prevent Tat interaction with mouse cyclin T1 and severely compromise HIV-1 replication in mouse cells. We investigated whether transgenic mice expressing human cyclin T1 under the control of a murine CD4 promoter/enhancer cassette that directs gene expression to CD4+ T lymphocytes and monocytes/macrophages (hu-cycT1 mice) would display Tat responsiveness in their CD4-expressing mouse cells and selectively increase HIV-1 production in this cellular population, which is infected primarily in HIV-1-positive individuals. To this end, we crossed hu-cycT1 mice with JR-CSF transgenic mice carrying the full-length HIV-1JR-CSF provirus under the control of the endogenous HIV-1 long terminal repeat and demonstrated that human cyclin T1 expression is sufficient to support Tat-mediated transactivation in primary mouse CD4 T lymphocytes and monocytes/macrophages and increases in vitro and in vivo HIV-1 production by these stimulated cells. Increased HIV-1 production by CD4+ T lymphocytes was paralleled with their specific depletion in the peripheral blood of the JR-CSF/hu-cycT1 mice, which increased over time. In addition, increased HIV-1 transgene expression due to human cyclin T1 expression was associated with increased lipopolysaccharide-stimulated monocyte chemoattractant protein 1 production by JR-CSF mouse monocytes/macrophages in vitro. Therefore, the JR-CSF/hu-cycT1 mice should provide an improved mouse system for investigating the pathogenesis of various aspects of HIV-1-mediated disease and the efficacies of therapeutic interventions.

* Corresponding author. Mailing address: Albert Einstein College of Medicine, Forschheimer Building, Room 408, 1300 Morris Park Avenue, Bronx, NY 10461. Phone: (718) 430-2156. Fax: (718) 430-8972. E-mail: hgoldste{at}aecom.yu.edu.

{dagger} These authors contributed equally to this paper.

Journal of Virology, February 2006, p. 1850-1862, Vol. 80, No. 4
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.4.1850-1862.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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