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Characterising lentiviral host interactions

Perry, Stephen Oliver; (2020) Characterising lentiviral host interactions. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Previously it was thought that the HIV-1M capsid undergoes rapid and spontaneous disassembly upon entering the cytoplasm. We now hypothesise that the HIV-1M capsid remains intact as it traverses the cytoplasm and plays a role in coordinating several stages in the life cycle via interactions with host cell proteins. These host proteins, which are essential for optimal infection, are termed cofactors. Here we investigate lentivirus-cofactor interactions, focusing on the cofactors IP6 and CypA. Recently it has been found that the abundant inositol deviate IP6 is able to drive immature particle formation and stabilises the mature capsid core for HIV-1M. Taking a comparative virology approach, in combination with phylogenetic and mutagenesis studies, we investigated whether the use of IP6 is conserved throughout the lentivirus lineage or whether it is a specific cofactor for HIV-1M. We provide evidence that IP6 usage is conserved throughout the lentiviral lineage, via the mutagenesis of the IP6 binding site within the capsid of diverse lentiviruses, and is essential for particle production and reverse transcription. Furthermore, we investigated CypA usage across the lentivirus lineage. We show that CypA usage is a feature which has evolved along the SIVCpz-HIV-1M branch, as replication of the parental SIVCpz virus to HIV-1M is independent of CypA. We also show that CypA usage in HIV-1M can be influenced by the position of the capsid NTD beta-hairpin. Finally, we investigate cellular factors which can influence HIV-1M CypA dependency in cell lines. Focusing on the cellular nuclease TREX-1, we manipulate its expression levels and measured CypA dependency of HIV-1M and the parental SIVCpz. We found that TREX-1 expression levels do no influence CypA dependency of either HIV-1M or SIVCpz.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Characterising lentiviral host interactions
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: https://discovery.ucl.ac.uk/id/eprint/10092239
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