UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

The role of the envelope cytoplasmic tail in Lentiviral replication

Haider, Tafhima; (2021) The role of the envelope cytoplasmic tail in Lentiviral replication. Doctoral thesis (Ph.D), UCL (University College London). Green open access

[thumbnail of Tafhima Haider_Thesis_FINAL.pdf]
Preview
Text
Tafhima Haider_Thesis_FINAL.pdf - Accepted version

Download (60MB) | Preview

Abstract

The envelope glycoprotein (Env) of lentiviruses plays an essential role in viral replication. Env is expressed on the plasma membrane of infected cells and is incorporated into budding virions, where it acts as the viral entry protein, binding to the CD4 receptor and coreceptors (CCR5 or CXCR4) on target cells to mediate attachment, fusion and entry of the viral capsid. Functional Env is a heterotrimeric structure composed of the receptor- binding surface subunit (gp120) and the transmembrane subunit (gp41) that contains the fusion peptide, a transmembrane domain and a cytoplasmic tail (CT). The HIV EnvCT is approximately 150 amino acids long, whereas the EnvCT of retroviruses are considerably shorter (approximately 50 amino acids). Conservation of the length of lentiviral EnvCTs suggests the presence of key determinants, many of which remain undefined, that are essential for efficient viral replication and spread. Previous studies have reported that HIV-2 and several SIVs truncate their EnvCT in vitro in order to gain a replicative advantage, although how this provides an advantage is currently unknown. To explore the biology of the EnvCT, HIV-1 and HIV-2 viruses with a truncated EnvCT were produced by site-directed mutagenesis and the requirement of the EnvCT has been explored in the context of viral replication, evasion of antiviral restriction factors and activation of signalling pathways. Data in this thesis show that HIV-1 and HIV-2 viruses have differential requirements for the long EnvCT, in a cell-type dependent manner. Whilst HIV-1 required a long EnvCT for efficient replication and spread in T cells, HIV-2 replication was not dependent on the EnvCT. This difference primarily mapped to differences in Env incorporation into virions, which is known to be a key determinant of infectivity. Notably, EnvCT truncation conferred resistance to two potent virus entry- targeting restriction factors, SERINC5 and IFITM. Further, results suggest that truncation of the EnvCT alters the susceptibility of virions to inhibition by neutralising antibodies. Together, this work provides new mechanistic insight into the role of the EnvCT in evasion of innate antiviral defences, revealing how viruses balance competing factors to adapt to their niche in the presence of differing selection pressures.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The role of the envelope cytoplasmic tail in Lentiviral replication
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/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/10132167
Downloads since deposit
9Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item