title: 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.
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.
authors.affiliation: Albert Einstein College of Medicine, Forschheimer Building, Room 408, 1300 Morris Park Avenue, Bronx, NY 10461, USA. hgoldste@aecom.yu.edu
authors.forename: Jinglin
authors.initials: J
authors.lastname: Sun
authors.forename: Timothy
authors.initials: T
authors.lastname: Soos
authors.forename: Vineet N
authors.initials: VN
authors.lastname: Kewalramani
authors.forename: Kristin
authors.initials: K
authors.lastname: Osiecki
authors.forename: Jian Hua
authors.initials: JH
authors.lastname: Zheng
authors.forename: Laurie
authors.initials: L
authors.lastname: Falkin
authors.forename: Laura
authors.initials: L
authors.lastname: Santambrogio
authors.forename: Dan R
authors.initials: DR
authors.lastname: Littman
authors.forename: Harris
authors.initials: H
authors.lastname: Goldstein
mesh_terms: D000818:Animals; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology*; D056906:Cyclin T; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D016655:HIV Core Protein p24 / Q000032:analysis; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D022423:Myeloid Cells / Q000378:metabolism / Q000821:virology*; D011533:Proviruses / Q000235:genetics; D013154:Spleen / Q000821:virology
chemical_list: C503684:CCNT1 protein, human; D056906:Cyclin T; D016213:Cyclins; D016655:HIV Core Protein p24; D008070:Lipopolysaccharides; D016178:Granulocyte-Macrophage Colony-Stimulating Factor