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Peter M. Mazari
B. A. Rutgers University 2005
Thesis Advisor: Monica Roth, Ph.D.
Graduate Program in Biochemistry & Molecular Biology
CABM - Room 010
Friday, August 20, 2010
The ability to direct viral entry would allow for specific gene delivery and make retroviral gene therapy a much more practical therapeutic option. By randomizing a small stretch in the receptor-binding domain of the feline leukemia virus Envelope protein (Env), libraries of Env proteins can be developed and screened for functional isolates on any target cell. This method has led to the discovery of several novel Envs which utilize receptors outside of the normal FeLV interference group. The study of these isolates will provide valuable information regarding the Env-Receptor interaction and the clinical potential of this and other retargeting methods.
In the studies contained herein we have examined two such isolates, CP and L1. Each provides its own intriguing qualities. CP produces very high titers and strong receptor binding. L1 has a very narrow tropism and may specifically target transformed cells. The primary means of study was examining the effects of specific mutations within the randomized receptor binding domain and the subsequent effects on viral titers and receptor binding.
Additionally, the construction and screening of a cDNA library led to the isolation of the receptor for CP, and revealed that this Env utilizes the same host receptor as the distantly related retrovirus, porcine endogenous retrovirus A (PERV-A). This allowed for deeper analysis of the CP-receptor interaction in direct comparison to the naturally evolved interaction between the receptor and PERV-A.
Together these studies have shed light onto the types of interactions taking place between the virus and its receptor. Additionally, studies on the CP receptor have highlighted the importance of the receptor contributions during viral entry and suggest that only certain surface proteins will provide the necessary qualities to permit this process. Without these characteristics viral targeting may only result in receptor binding and not targeted infection. All of these studies have helped to validate the use of randomized libraries as an efficient means by which to retarget viral entry and isolate novel Envs.