or
Continue with FacebookLooking to list your PhD opportunities? Log in here.
This project is no longer listed on FindAPhD.com and may not be available.
Click here to search FindAPhD.com for PhD studentship opportunities
Dr J Mankouri
Prof M Harris
Applications accepted all year round
Self-Funded PhD Students Only
About the Project
HIV establishes a chronic infection in human CD4-positive T-helper cells, macrophages and myeloid dendritic cells and has evolved to encode multifunctional accessory proteins that manipulate host biology to promote virus survival. During HIV infection maintaining the viability of infected cells is vital for viral pathogenesis. In this context, the HIV Nef protein modulates host cell physiology to provide an optimal environment for viral persistence. Work in our laboratory mainly focuses on understanding the interactions of viral proteins with their respective host cells. Nef is one such accessory protein and a key determinant for viral pathogenesis.
Ion channels play a key role in the regulation of all aspects of cell physiology including cell proliferation and apoptosis. We recently demonstrated the first specific involvement of host cell ion channel function in the lifecycle of a virus. We showed that the hepatitis C virus non structural 5A protein (NS5A) was capable of inhibiting the activity of a host cell liver expressed K+ channel; Kv2.1, in order to maintain the survival of the infected hepatocytes (Mankouri et al PNAS 2009). Preliminary data suggests that Nef also inhibits the activation of Kv2.1. This may be pertinent to the HIV lifecycle as Nef is known to promote the long term survival of HIV infected T lymphocytes.
The studentship will thus use a combination of electrophysiological and cell biological assays to characterize the function of Kv2.1 and other ion channels in HIV infected cells. The main focus will be towards understanding how these host cell ion channels impact on the HIV lifecycle. The increasing knowledge of host cell targets for HIV interactions will be essential for the discovery of new targets that could be used to design new HIV therapeutic strategies.
The studentship will provide training in a wide range of electrophysiology, molecular biology, cell culture and virological techniques. Research in this area will provide novel information on how the ion channels expressed in all cells of the human body regulate the life cycle of HIV. This may ultimately lead to the identification of specific antiviral targets to inhibit viral–ion channel interactions,
The project will be jointly supervised by Dr Jamel Mankouri and Professor Mark Harris.
Ion channels play a key role in the regulation of all aspects of cell physiology including cell proliferation and apoptosis. We recently demonstrated the first specific involvement of host cell ion channel function in the lifecycle of a virus. We showed that the hepatitis C virus non structural 5A protein (NS5A) was capable of inhibiting the activity of a host cell liver expressed K+ channel; Kv2.1, in order to maintain the survival of the infected hepatocytes (Mankouri et al PNAS 2009). Preliminary data suggests that Nef also inhibits the activation of Kv2.1. This may be pertinent to the HIV lifecycle as Nef is known to promote the long term survival of HIV infected T lymphocytes.
The studentship will thus use a combination of electrophysiological and cell biological assays to characterize the function of Kv2.1 and other ion channels in HIV infected cells. The main focus will be towards understanding how these host cell ion channels impact on the HIV lifecycle. The increasing knowledge of host cell targets for HIV interactions will be essential for the discovery of new targets that could be used to design new HIV therapeutic strategies.
The studentship will provide training in a wide range of electrophysiology, molecular biology, cell culture and virological techniques. Research in this area will provide novel information on how the ion channels expressed in all cells of the human body regulate the life cycle of HIV. This may ultimately lead to the identification of specific antiviral targets to inhibit viral–ion channel interactions,
The project will be jointly supervised by Dr Jamel Mankouri and Professor Mark Harris.
Funding Notes
Self-funded students: International or domestic self-funded or scholarship/fellowship PhD students are welcome to apply. Bench fees will be required if you are self-funded.
References
Selected References
(1) Mankouri J, Harris M. Viruses and the fuel sensor: the emerging link between AMPK and virus replication. Rev Med Virol. 2011 21:205-12.
(2) Dallas ML, Boyle JP, Milligan CJ, Sayer R, Kerrigan TL, McKinstry C, Lu P, Mankouri J, Harris M, Scragg JL, Pearson HA, Peers C. Carbon monoxide protects against oxidant-induced apoptosis via inhibition of Kv2.1. FASEB J. 2011 25:1519-30.
(3) Mankouri J, Tedbury PR, Gretton S, Hughes ME, Griffin SD, Dallas ML, Green KA, Hardie DG, Peers C, Harris M. Enhanced hepatitis C virus genome replication and lipid accumulation mediated by inhibition of AMP-activated protein kinase. Proc Natl Acad Sci U S A. 2010 22:11549-54.
(4) Mankouri J, Fragkoudis R, Richards KH, Wetherill LF, Harris M, Kohl A, Elliott RM, Macdonald A. Optineurin negatively regulates the induction of IFNbeta in response to RNA virus infection. PLoS Pathog. 2010 19:e1000778.
(5) Milward A, Mankouri J, Harris M. Hepatitis C virus NS5A protein interacts with beta-catenin and stimulates its transcriptional activity in a phosphoinositide-3 kinase-dependent fashion. J Gen Virol. 2010 91:373-81.
(6) Gamlen T, Richards KH, Mankouri J, Hudson L, McCauley J, Harris M, Macdonald A. Expression of the NS3 protease of cytopathogenic bovine viral diarrhea virus results in the induction of apoptosis but does not block activation of the beta interferon promoter.
J Gen Virol. 2010 91:133-44.
(7) Mankouri J, Dallas ML, Hughes ME, Griffin SD, Macdonald A, Peers C, Harris. Suppression of a pro-apoptotic K+ channel as a mechanism for hepatitis C virus persistence. M. Proc Natl Acad Sci U S A. 2009 15:15903-8.
(8) Taneja TK, Mankouri J, Karnik R, Kannan S, Smith AJ, Munsey T, Christesen HB, Beech DJ, Sivaprasadarao A. Sar1-GTPase-dependent ER exit of KATP channels revealed by a mutation causing congenital hyperinsulinism. Hum Mol Genet. 2009 18:2400-13.
(9) Mankouri J, Milward A, Pryde KR, Warter L, Martin A, Harris M.A comparative cell biological analysis reveals only limited functional homology between the NS5A proteins of hepatitis C virus and GB virus B. J Gen Virol. 2008 89:1911-20.
(10) Mankouri J, Griffin S, Harris M. The hepatitis C virus non-structural protein NS5A alters the trafficking profile of the epidermal growth factor receptor. Traffic. 2008 9:1497-509.
(1) Mankouri J, Harris M. Viruses and the fuel sensor: the emerging link between AMPK and virus replication. Rev Med Virol. 2011 21:205-12.
(2) Dallas ML, Boyle JP, Milligan CJ, Sayer R, Kerrigan TL, McKinstry C, Lu P, Mankouri J, Harris M, Scragg JL, Pearson HA, Peers C. Carbon monoxide protects against oxidant-induced apoptosis via inhibition of Kv2.1. FASEB J. 2011 25:1519-30.
(3) Mankouri J, Tedbury PR, Gretton S, Hughes ME, Griffin SD, Dallas ML, Green KA, Hardie DG, Peers C, Harris M. Enhanced hepatitis C virus genome replication and lipid accumulation mediated by inhibition of AMP-activated protein kinase. Proc Natl Acad Sci U S A. 2010 22:11549-54.
(4) Mankouri J, Fragkoudis R, Richards KH, Wetherill LF, Harris M, Kohl A, Elliott RM, Macdonald A. Optineurin negatively regulates the induction of IFNbeta in response to RNA virus infection. PLoS Pathog. 2010 19:e1000778.
(5) Milward A, Mankouri J, Harris M. Hepatitis C virus NS5A protein interacts with beta-catenin and stimulates its transcriptional activity in a phosphoinositide-3 kinase-dependent fashion. J Gen Virol. 2010 91:373-81.
(6) Gamlen T, Richards KH, Mankouri J, Hudson L, McCauley J, Harris M, Macdonald A. Expression of the NS3 protease of cytopathogenic bovine viral diarrhea virus results in the induction of apoptosis but does not block activation of the beta interferon promoter.
J Gen Virol. 2010 91:133-44.
(7) Mankouri J, Dallas ML, Hughes ME, Griffin SD, Macdonald A, Peers C, Harris. Suppression of a pro-apoptotic K+ channel as a mechanism for hepatitis C virus persistence. M. Proc Natl Acad Sci U S A. 2009 15:15903-8.
(8) Taneja TK, Mankouri J, Karnik R, Kannan S, Smith AJ, Munsey T, Christesen HB, Beech DJ, Sivaprasadarao A. Sar1-GTPase-dependent ER exit of KATP channels revealed by a mutation causing congenital hyperinsulinism. Hum Mol Genet. 2009 18:2400-13.
(9) Mankouri J, Milward A, Pryde KR, Warter L, Martin A, Harris M.A comparative cell biological analysis reveals only limited functional homology between the NS5A proteins of hepatitis C virus and GB virus B. J Gen Virol. 2008 89:1911-20.
(10) Mankouri J, Griffin S, Harris M. The hepatitis C virus non-structural protein NS5A alters the trafficking profile of the epidermal growth factor receptor. Traffic. 2008 9:1497-509.
How good is research at University of Leeds in Biological Sciences?
Research output data provided by the Research Excellence Framework (REF)
Click here to see the results for all UK universitiesProject supervisors
Dr J Mankouri's profile is coming soon
View other supervisors at University of LeedsCareer overview
Professor Mark Harris obtained a BSc from Plymouth and a PhD from the Institute of Virology in Glasgow in 1987. He held a post-doctoral position with Dr Possee at the NERC Institute of Virology in Oxford from 1987 to 1988. Subsequently, he worked as a PostDoctoral Research Fellow at the MRC Retrovirus Research Laboratory in Glasgow from 1988 to 1993. From 1993 to 1998, he held an MRC Senior Research Fellowship at the MRC Retrovirus Laboratory in Glasgow, during which he moved to the Department of Microbiology at the University of Leeds in 1997. Professor Harris is currently a Professor of Virology at the University of Leeds, where he focuses on RNA viruses, virus-host interactions, virus replication and assembly, and antiviral drug development.
Research interests
Professor Harris''s research focuses on virology, specifically the interactions between viruses and their hosts, as well as mechanisms of virus replication and assembly. His work includes significant studies on hepatitis C virus (HCV), Chikungunya virus (CHIKV), Ebolavirus (EBOV), and SARS-CoV-2. In relation to HCV, Professor Harris''s laboratory investigates the molecular mechanisms of HCV genome replication and the assembly of new virus particles, with a particular emphasis on virus-host interactions. A key area of interest is the role of the HCV NS5A protein, which is crucial for both genome replication and the assembly of infectious virus particles. Recent findings have highlighted a novel function of NS5A in antagonising the interferon-induced kinase PKR, and ongoing studies aim to identify the molecular effectors involved. Professor Harris is also exploring the characteristics of HCV genotype 3, which poses challenges such as higher resistance to direct acting antivirals and more severe disease outcomes. His lab is utilising newly developed culture systems to study NS5A''s role in this genotype. For CHIKV, which has seen a resurgence in global epidemics, Professor Harris''s research focuses on the viral protein nsP3. His studies aim to characterise the functions of nsP3 through mutagenesis and to analyse virus replication in human and mosquito cells. The research employs advanced techniques like proteomics and super-resolution microscopy to identify host proteins or RNAs that interact with nsP3. In collaboration with colleagues, Professor Harris is also working on Ebolavirus, utilising computer-aided molecular design and synthetic chemistry to develop small molecules that target the EBOV nucleocapsid protein. This work aims to create effective therapeutic options against EBOV, particularly in light of the challenges posed by the need for high containment levels for EBOV propagation. Additionally, his research on SARS-CoV-2 involves identifying novel inhibitors of the virus''s nsp14 exoribonuclease, with the goal of finding effective treatments in conjunction with existing antiviral drugs. Overall, Professor Harris''s research is supported by a Wellcome Discovery Award and contributes to the broader fields of virology and molecular biology through collaborative efforts and innovative methodologies.
Virology
RNA Viruses
Virus-Host Interactions
Virus Replication
Virus Assembly
Hepatitis C Virus
Chikungunya Virus
Ebolavirus
Antiviral Drug Development
PKR
NS5A Protein
Molecular Mechanisms
Genotype 3 HCV
Proteomics
iCLIP
Super-Resolution Microscopy
Natural Products
SARS-CoV-2
Computer-Aided Molecular Design
Small Molecules
Gene Expression
Therapeutic Options
Infectious Diseases.
Find a scholarship to fund your dream Masters
Sign in to view and filter all scholarship opportunities
or
Continue with Facebook