Prof Mark Harris

Mark Harris is Professor of Virology in the School of Molecular and Cellular Biology. Since obtaining a PhD in Virology from the University of Glasgow he has worked on a variety of viruses. In 1993 he was awarded an MRC Senior AIDS Research Fellowship to work on the HIV-1 Nef protein at the University of Glasgow. He moved to Leeds in 1997 where he took up a lectureship position and established a research portfolio in hepatitis C virus. In 2011 he was awarded a prestigious Wellcome Trust Senior Investigator Award to continue work on hepatitis C virus.

Research Areas: Structural Studies on HIV-1 Nef Protein

1) Studies on the replication and assembly of hepatitis C virus

Hepatitis C virus (HCV) is an important human pathogen that infects an estimated 170 million people worldwide. We are interested in understanding the molecular mechanisms of viral genome replication and assembly, with a particular focus on the virus-host interactions that underpin these processes. The ultimate goal of this research is to identify new targets for the development of novel antivirals.

Specific projects include:

Analysis of the structure and composition of the RNA replication complex.
We are using both proteomic and imaging techniques to probe the multiprotein complex that replicates the viral genome. For example – purifying the nascent RNA from infected cells and identifying the associated proteins by mass spectrometry, and genetically tagging the virus to enable either high resolution EM or fluorescent imaging. In collaboration with Dr Jamel Mankouri (Leeds) these studies will exploit the recently installed confocal microscope with live cell imaging capability in the category III containment facility – a unique resource within the UK for the study of HCV.

Functional studies on the non-structural NS5A protein.
NS5A is a phosphoprotein that plays as yet undefined but essential roles in both genome replication and virus assembly. We are using a combination of techniques to investigate these roles, for example mutagenesis to define key residues, protein-protein interaction analysis to identify cellular (and viral) partners and mass spectrometry to identify phosphorylation sites. We are also investigating the interaction of NS5A with viral RNA, with the aim of identifying RNA–binding motifs within NS5A and defining the RNA sequences that are bound by the protein.

Application of structure-based drug design to develop new HCV therapeutics.
In collaboration with Prof Colin Fishwick (Chemistry) we are exploiting the existing structural information about HCV non-structural proteins (in particular NS2 and NS5A) to identify candidate antiviral compounds. These will be tested using established methodologies (sub-genomic replicons, infectious virus assays) and then subject to iterative SAR to optimise their potential to inhibit virus replication.

2) HIV Nef studies

In addition to studies on HCV, we are using structure-based drug design to design inhibitors of the HIV-1 Nef protein. Nef is a key protein in HIV pathogenesis and we have determined the crystal structure of the full-length myristoylated HIV-1 Nef (in collaboration with Dr Joe Jaeger, Albany, NY). These studies have identified compounds that have been assayed using FACS to demonstrate inhibition of Nef induced CD4 and MHC-I down-modulation, and shown by ITC to bind to Nef.