Jacobs, Caron Adrienne; (2018) The nanoscale organisation of HIV cell surface receptors CD4 and CCR5. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The plasma membrane serves as the cell’s front line for interactions with, and response to, the external environment. The molecular mechanisms and regulation of cellular responses to extracellular signals are determined by the spatial organisation and dynamics of the various components comprising the plasma membrane. CD4 and CCR5 are two key cell surface molecules with important roles in immune cell function and regulation. They are also co-opted as the primary receptor and a co-receptor, respectively, by HIV. Biochemical studies have provided a detailed understanding of the molecular mechanisms of these interactions. Until recently, however, the small scale and rapid dynamics of these interactions has meant that a detailed view of the topology of the cell membrane and the organisation of receptors first encountered by the virus has been beyond the resolving power of available tools. The increasing capabilities of the emerging and rapidly developing super-resolution microscopy technologies are now optimally poised for us to address some of these questions. In this work, I have applied single molecule localization microscopy to unveil some of the nanoscale organisational properties of the cell surface receptors CD4 and CCR5. I have worked on the development of small labelling probes for CD4 and addressed some of the key aspects of sample preparation and labelling that can artificially alter the distribution of membrane associated target molecules. Here I report the first quantitative characterisation of the nanoscale organisation of CD4 and CCR5 in lymphoid cell plasma membranes, as well as how this organisation changes under different conditions, such as in response to cell signal-mimicking stimulation, or exposure to HIV envelope. This approach to characterising membrane receptor organisation can be further applied to in-depth studies of early host cell-virus interactions, as well as to other cell surface receptors and their organisation in the context of key cellular functions.

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