Retroviral infection requires an initial interaction between the host cell and the virion. This interaction is predominantly mediated by an envelope (env) protein exposed on the external face of the virion. For gammaretroviruses, such as feline leukemia virus (FeLV), the receptor-binding domain (RBD) is located in the N terminus of env. The RBD forms a distinct domain that is sufficient for binding to the host receptor, but is inefficient in the absence of the corresponding C terminal env, Cdomain, sequence in viral infection studies. I developed a series of hybrid constructs between subgroup C, A and T FeLVs that use distinct receptors for infection to determine the role of Cdom in FeLV binding and infection. Using this approach, I have shown that the C domain (Cdom) of FeLV-C env forms a second receptor-binding domain, distinct from its RBD, which is critical for efficient binding and infection of FeLV-C to host cells expressing FLVCR1. I propose that this mechanism of interaction is conserved for all gammaretroviruses. My results could have important implications for designing gammaretrovirus vectors that can efficiently infect specific target cells. Upon infection with FeLV-C virus, cats develop a disease known as pure red cell aplasia (PRCA). This disease is characterized by a defect in erythropoeisis that results in a decreased number of mature erythroid cells. PRCA has been suggested to be caused by the FeLV-C env binding to and disrupting the host receptor, FLVCR1. Interestingly, feline PRCA is clinically identical to Diamond Blackfan Anemia (DBA), a fatal congenital anemia characterized by a specific disruption in erythroid progenitor cellular development. I show that erythroid cells from five DBA patients exhibit low levels of total FLVCR1 transcript expression. In addition, the DBA patients express unique alternatively spliced FLVCR1 transcripts. These alternatively spliced transcripts encode FLVCR1 proteins that are defective in their cellular expression, cell surface localization, and receptor function. Taken together, I propose that the specific anemia observed in DBA is caused by decreased levels of functional FLVCR1 protein due to lowered and alternative splicing of FLVCR1 transcript.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/17823 |
| Date | 25 September 2009 |
| Creators | Rey, Michelle |
| Contributors | Tailor, Chetankumar |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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