Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
TRANSGENIC MOUSE MODEL OF HUMAN IMMUNODEFICIENCY VIRUS (HIV)-INDUCED KAPOSI'S SARCOMA
The Human Retroviruses. Gallo RC and Jay G, eds. San Diego, Academic Press, p. 277-94, 1991.. Unique Identifier : AIDSLINE ICDB/92678731 Vogel J; Rhim JA; Jay DB; Jay G; Jerome H. Holland Lab., American Red Cross, Rockville, MD 20855
Abstract:
In the study of HIV, an alternative to finding animals that can be successfully infected with HIV is to derive animal models by placing the viral genome or segments of it directly into the germline of animals. One such model has been developed by microinjecting a chimeric construct containing the HIV tat gene under the control of viral long terminal repeat (LTR) into the germ line of mice. The development and results of studies with this model are reviewed, including rationale for the transgenic approach to the study of viral pathogenesis; derivation of transgenic mice with the HIV tat gene; development skin lesions in the transgenic tat mice; association between HIV infection and Kaposi's sarcoma (KS); similarities between murine skin lesions and human KS; suggested mechanisms for the development of KS; and a proposed model for the etiology of KS. The LTR sequence used included both the positive and negative regulatory elements in the U3 region and the trans-acting responsive (TAR) sequence located within the R region. This will support tat trans-activation of the LTR. Despite the presence of the tat gene in all cell types in the resulting transgenic mice, however, tat mRNA has been detected only in the skin of these animals. Skin lesions develop in tat transgenic mice that have a marked resemblance to those of KS in humans. By 15-24 mo of age, about 1/6 male mice had developed distinct nodules, which were particularly noted for the erythematous nature of these tumors. Perhaps the most puzzling observation in these transgenic mice is that the tumors that developed did not express the transgenic tat gene, implying that the Tat protein is not required for the maintenance of neoplastic growth. Focal areas of thickened, hyperplastic epidermis consisting of poorly differentiated cells are seen even when mice are very young. In response to trans-activation by the Tat protein, the hyperplastic epidermal cells may release signals, most likely specific cytokines, which can induce a subset of cells in the underlying dermis to proliferate. KS thus may represent communication between epidermis and dermis that has gone astray. An imbalance in the release of certain cytokines by specific cells in the skin may induce inappropriate responses by different target cells that lead to the development of disease. (68 Refs)
Keywords: Animal Cell Transformation, Neoplastic/GENETICS/PATHOLOGY Gene Expression Regulation, Viral/*PHYSIOLOGY Genes, tat/GENETICS/PHYSIOLOGY Human HIV/*GENETICS/PATHOGENICITY Mice Mice, Transgenic Murine Acquired Immunodeficiency Syndrome/*GENETICS/PATHOLOGY Sarcoma, Kaposi's/*GENETICS/PATHOLOGY Skin/PATHOLOGY Skin Neoplasms/*GENETICS/PATHOLOGY MONOGRAPH REVIEW
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Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
