Harrison, Lauren; (2020) Design and evaluation of inhibitors targeting HIV capsid and cofactors. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Our favoured model is that upon entry into the target cell, the HIV-1 capsid remains intact, performing crucial functions within the early viral lifecycle. This includes, binding to cofactors, protecting the viral genome, regulating reverse transcription and entry into the nucleus. Five of the six current HIV-1 antiretrovirals target early lifecycle events, from entry to integration. Due to its multitude of functions, capsid and its cofactors are an attractive target for antiviral inhibitors, yet there is no licensed anti-HIV-1 drug targeting these. Our aim is to develop potent inhibitors, which perturb capsid integrity and function, to push HIV-1 to adopt different, less successful behaviour. We are calling our first inhibitor series the allosteres, as we hypothesise that they are breaking allosteric mechanisms of the capsid. We have established that our highly potent allosteres when bound to HIV-1 capsid are causing significant activation of the innate immune system. As well as developing new potent HIV-1 antiretroviral therapies, these allosteres will be used as probes of capsid function confirming how vital it is for the capsid to remain whole within the cytoplasm leading to productive infection. Additionally, our second series of inhibitors are cyclophilin A targeting. Although cyclophilin A’s cellular functions have remained elusive, we know a number of unrelated viruses recruit and exploit this host protein as a cofactor. When the interaction between capsid and cyclophilin A is prevented, it leads to activation of innate immune sensing pathways within macrophages. Although, it remains incompletely understood how cyclophilin A is protecting the capsid, we aim to use our inhibitors to probe cyclophilin A roles within the early viral lifecycle. Overall our investigations confirm the roles of capsid and its interaction with cyclophilin A, demonstrating that by using inhibitors to directly target and manipulate these roles can significantly disrupt infection. Hopefully, the merits of this research can act as a paradigm for the development of capsid and cofactors inhibitors, not only for HIV-1, but also for many other viruses dependent on these mechanisms.

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