Recombinant MHV-68 as a model system for Kaposi’s sarcoma-associated herpesvirus vaccine development
Human herpesvirus 8 (HHV-8) or Kaposi Sarcoma Associated Herpesvirus (KSHV) is the causative agent of Kaposi’s sarcoma (KS). The prevalence of KS varies, although emergence increases considerably with HIV co-infection making it one of the most common cancers of HIV patients and sub-Saharan African men. In immunocompetent individuals KSHV infection is usually asymptomatic; however, in immunocompromised patients such as transplant recipients, infection poses an increased risk for the development of aggressive tumours. Current therapies aim to alleviate symptoms and are unable to eliminate the latent infection residing in B cells. A vaccine for treatment and prevention KSHV would therefore be of importance.
Binding and entry of KSHV to the host cell is a complex process which includes the involvement of multiple viral surface glycoproteins. Glycoprotein K8.1 (gpk8.1) has been shown to be the target of neutralising antibodies and to be vital for B cell infection, and could therefore provide a target for the development of a clinically relevant active and/or passive vaccine for KSHV infection prevention and treatment. In order to achieve this, we aim to produce a neutralising antibody response against KSHV in mice following immunisation with recombinant gpk8.1 for the development of an active vaccine. In addition, Trianni mice, capable of producing humanised antibodies, will be immunised with recombinant gpk8.1 for the purpose of producing monoclonal antibodies with reduced immunogenicity for passive vaccine development.
KSHV is species specific and there currently exists no animal model for the study of the virus or developed treatments. Thus, the final aim of the project will be to develop a mouse model for the testing of vaccine efficacy. Murine gammaherpesvirus 68 (MHV-68) is a rodent herpesvirus in which glycoprotein 150 (gp150) is the functional and positional analogue to human gpk8.1. Hence, MHV-68 will be mutagenised to replace the gp150 ectodomain with KSHV gpk8.1. Prior to infection with mutagenised MHV-68, mice will be immunised either actively with recombinant gpk8.1 or passively with humanised monoclonal antibodies to determine whether neutralising capacity is sufficient to combat infection, particularly in preventing latent infection of B cells.
