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, Timothy Soos, Vineet N. KewalRamani, Kristin Osiecki, Jian Hua Zheng, Laurie Falkin, Laura Santambrogio, Dan R. Littman, Harris Goldstein

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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-1 JR-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.

Original languageEnglish (US)
Pages (from-to)1850-1862
Number of pages13
JournalJournal of Virology
Volume80
Issue number4
DOIs
StatePublished - Feb 2006

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Cyclin T
proviruses
Proviruses
cyclins
Myeloid Cells
Human immunodeficiency virus 1
monocytes
Transgenic Mice
HIV-1
Monocytes
tropics
T-lymphocytes
genetically modified organisms
T-Lymphocytes
gene expression
mice
cells
Transcriptional Activation
transcriptional activation
Macrophages

ASJC Scopus subject areas

  • Immunology

Cite this

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. / Sun, Jinglin; Soos, Timothy; KewalRamani, Vineet N.; Osiecki, Kristin; Zheng, Jian Hua; Falkin, Laurie; Santambrogio, Laura; Littman, Dan R.; Goldstein, Harris.

In: Journal of Virology, Vol. 80, No. 4, 02.2006, p. 1850-1862.

Research output: Contribution to journalArticle

Sun, Jinglin ; Soos, Timothy ; KewalRamani, Vineet N. ; Osiecki, Kristin ; Zheng, Jian Hua ; Falkin, Laurie ; Santambrogio, Laura ; Littman, Dan R. ; Goldstein, Harris. / 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. In: Journal of Virology. 2006 ; Vol. 80, No. 4. pp. 1850-1862.
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abstract = "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-1 JR-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.",
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T1 - 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

AU - Sun, Jinglin

AU - Soos, Timothy

AU - KewalRamani, Vineet N.

AU - Osiecki, Kristin

AU - Zheng, Jian Hua

AU - Falkin, Laurie

AU - Santambrogio, Laura

AU - Littman, Dan R.

AU - Goldstein, Harris

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