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Title: The effects of HIV-1, HCV and Ebola virus envelope proteins on modulating viral phenotypes and activity
Author: Mckay, L.
ISNI:       0000 0004 7970 4034
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2019
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The aim of this thesis is to present original research concerning co-infection between human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) as well as HIV-1 and Ebola virus (EBOV). This will specifically include studies with regards to understand how the envelope (Env) glycoproteins of HCV (E1E2 and E2 alone) can modulate the activity of the HIV-1 long terminal repeat (LTR) leading to a down-modulation in HIV-1 viral production and infectivity. In addition, the novel theory of viral Env trans-complementation (wherein a single viral particle can carry more than one Env) and the subsequent modulation of viral phenotypes will be explored. An estimated 2.3 million individuals world-wide are co-infected with both HIV-1 and HCV, therefore the concept of LTR modulation via the HCV Env protein is both new and of great relevance. Understanding HCV E1E2 or E2 dependent modulation of intracellular signalling will also have implications in better elucidating the molecular processes influencing HIV1/HCV disease progression as well as other clinical implications associated with HCV infection. These include the modulation of immune responses or cancer development. Similarly, Env trans-complementation has only previously been studied with regards to observing the shuttling of Env proteins and not regarding the formation of dual Env expressing virions or the significance of this on modulating viral phenotypes. This is investigated with reference to the recent Ebola outbreaks as well as HIV-1/HCV co-infection. To assess the novel capabilities for E1E2/E2 related signalling modulation, the pseudo-typed virus system was employed. Populations of single or dual Env expressing viral particles with the HIV-1 backbone were created carrying HIV-1 gp120/gp41 Env (CCR5 or CXCR4 tropic) glycoproteins as well as the HCV E1E2 Env protein. It was observed that increasing concentrations of E1E2 led to a down-modulation of viral infectivity on the TZM-bl HIV-1 susceptible cell line. Trans-infection via DC-SIGN was not altered via co-expression of the HCV E1E2 protein and antibody neutralisation (by either anti-HIV-1 or anti-HCV) was only marginally affected. Significantly, it was observed that an increase in HCV E1E2 lead to a decrease in HIV-1 viral production when utilising the dual Env model. To further explore the role of HCV E1E2 on HIV-1/HCV co-infection, E1E2 and soluble E2 (sE2) alone were transfected along with a Luciferase expression plasmid under control of the HIV-1 LTR. A dose-dependent decrease in LTR promoter activity was observed and where the effect was correlated to NF-?B signalling but not activation. This was tested in a cross-HCV genotypic and HIV-1 subtype specific manner with some differences identified. Env trans-complementation was also investigated in relation to HIV-1/EBOV co-infection. A substantial increase in CCR5 HIV-1 infectivity was observed when complemented with an EBOV GP Env protein and modulation of both trans-infection via DC-SIGN and antibody neutralisation was documented. This included a reduction in the neutralisation potential of dual enveloped virus and an increase in viral infectivity in the presence of antibody. This study is considered in the context of EBOV recurrence as documented in recent outbreaks. The research presented here regarding the modulation of the HIV-1 LTR via HCV E1E2 or E2 and Env trans-complementation presents novel pathways by which viral phenotypes can be affected. Importantly, thisindicates new avenues of research regarding viral co-infection and discusses the implications for affecting disease progression and treatment in co-infected individuals.
Supervisor: Paxton, William ; Pollakis, Georgios Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral