Pennington, Daniel John; (1996) The analysis of the in vivo effects of the HIV-1 nef and tat regulatory genes using a transgenic mouse system. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Although it is widely accepted that the human immunodeficiency virus (HIV) is the aetiologic agent responsible for the acquired immunodeficiency syndrome (AIDS), the precise mechanisms that underlie the HIV-1-mediated destruction of the immune system are unclear. Nevertheless, one thing is certain, the breakdown of the host immune system must be caused by, or be the result of, the presence of a viral component(s). Two such viral components are the HIV-1 nef gene and the HIV-1 tat gene. Transgenic mouse models were generated to examine the in vivo interaction of the nef gene and the tat gene with a dynamic mammalian immune system. These genes were expressed in the majority of thymocytes and T-cells using the human CD2 regulatory elements. In CD2-nef transgenic mice, a downregulation of cell surface CD4 (to a region co-localising with a golgi-specific marker) in CD4/CD8 double positive thymocytes, and a significant loss of CD4 single positive thymocytes was observed. These mice also displayed a severe reduction in thymic cellularity, resulting from a partial block in the transition of CD44- CD25- I-thymocytes to a CD44- CD25-phenotype during early thymic differentiation. In CD2-tat transgenic mice activated T-cells were found to produce decreased levels of TNFβ, TGFβ and IL-4R mRNA. A decreased level of TNF protein was also detected. However, thymocyte development and mature T-cell proliferation responses appear normal, and no evidence of KS-like lesions or tumours were found in any mice at any age. The CD2-nef and CD2-tat transgenic mouse models described and discussed in this thesis suggest that both the HIV-1 ne/gene and the HIV-1 tat gene have a complex interaction with both developing thymocytes and mature T-cells. Therefore, these mouse models may provide an important tool for the detailed analysis of the in vivo effects that the expression of these HIV-1 regulatory genes have on the pathogenesis of an HIV-1 infection.

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