Turner, Sarah Kistler; (2000) In vivo studies of the Kaposi's sarcoma-associated herpesvirus (KSHV). Doctoral thesis (M.Phil), UCL (University College London).

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Abstract

Animal models of human disease are invaluable tools. They allow researchers to understand many aspects of human disease that can not be studied in vitro. With respect to viral diseases, these include initial stages of viral infection, viral load levels in various organs and viral and cellular gene expression patterns. In addition, transgenic animal models can be used to study the in vivo effects of one or more viral genes in the absence of the rest of the viral genome. The recently discovered Kaposi's sarcoma-associated herpesvirus (KSHV, also known as human herpesvirus 8 or HHV-8) (Chang et al, 1994) was the first human gamma-2 herpesvirus to be identified. It is causally linked to three diseases, Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). Humans appear to be the natural host for KSHV, and there is no evidence to suggest that any natural infection of animal species occurs. In addition, transmission of the virus to common laboratory animals has not been reported (Dittner et al., 1999). Because a suitable animal model of viral infection is not yet available, the study of KSHV biology has been greatly impeded. Transmission of KSHV to an animal species requires that the virus is able to permissively infect the host cells. In all animal species studied so far, this has not occurred. One way of bypassing the need for infection, and permitting the study of the in vivo effects of one or more viral genes, is the use of microinjection technology. With the aid of this technology, three different homozygous lines of transgenic mice were created: One containing the KSHV encoded K1 gene, another containing orfs 71 and 72 and a third containing orfs 71, 72, and 73. Southern blot analysis revealed that each line contained one integration site, and that the integration patterns varied. Transgene mRNA transcripts were detected in all lines by RT-PCR analysis, and Western blot analysis revealed that LNA and K-cyclin proteins could be detected in some lines. Some phenotypic analysis has also been carried out.

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