Mesner, Dejan;
(2020)
The role of Nef-mediated CD3 downmodulation during HIV-1 viral spread.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
HIV-1 most efficiently disseminates by direct cell-cell transmission that occurs at virological synapses (VS) formed between infected and uninfected CD4+ T cells. Previous work has shown that VS formation triggers antigen-independent T cell receptor (TCR) signalling in infected T cells to drive viral spread. Interestingly, the viral accessory protein Nef of HIV-2 and most SIV lineages, but not HIV-1, downmodulates CD3 - the signalling component of TCR complex. This impairs signalling at the immunological synapse and may interfere with antiviral responses and prevent aberrant immune activation. Why HIV-1 lost this potential immune evasion strategy remains incompletely understood. This question was addressed using chimeric HIV-1 viruses expressing SIVsmm Nef proteins and mutants thereof that differ specifically in their ability to downmodulate CD3. The results show that retained CD3 expression on infected cells resulted in enhanced viral cell-cell spread compared to viruses that downmodulate CD3 expression. Retained CD3 expression resulted in increased expression of functional envelope trimers (Env) on the surface of infected cells, increased Env incorporation into virions and thus increased virion infectivity, which was found to be the determinant for enhancement of viral spread. Increased Env expression and virion infectivity was shown to be dependent on VS formation and cell activation, thus explaining the role of CD3 and TCR signalling in this process. It was also observed that during cell cell spread the presence of CD3 on infected cells correlated with enhanced TCR signalling at the VS, increased cell activation, as well as increased cell death. In addition to SIVsmm, SIVmac and HIV-2 Nef chimeric viruses were also examined, as they originate from zoonotic transmissions from SIVsmm. Interestingly, SIVmac and HIV-2 Nef viruses did not show any differences in cell-cell spread, virion infectivity or cell activation that correlated with CD3 downmodulation as observed for SIVsmm Nef viruses. The reason for this remains unknown; however, it suggests that there may be additional species-specific Nef determinants that contribute to efficient viral spread. Taken together, the results suggest that HIV-1 might have lost Nef-mediated CD3 downmodulation activity to allow for more efficient viral replication while losing the ability to suppress T cell activation and cell death, which possibly contributes to increased viral pathogenicity of HIV-1.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The role of Nef-mediated CD3 downmodulation during HIV-1 viral spread |
| 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 > 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/10107824 |
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