Head of fruit fly in cross section

Kate Bishop group

Infection and replication of retroviruses

Retroviruses cause severe diseases, including immunodeficiency and cancer. The human immunodeficiency virus (HIV) is the most widely known retrovirus due to its impact on human health. The latest figures report that 33 million people globally are living with HIV/AIDS.

In 2006 a novel retrovirus called xenotropic MLV-related virus (XMRV) was isolated from patients with familial prostate cancer. Prostate cancer is the most prevalent cancer amongst men in the UK, and hereditary prostate cancer is thought to account for 9-15% of cases. More recently, XMRV has been identified in patients with chronic fatigue syndrome (CFS). At this time, it is not known whether these diseases are linked to infection by XMRV.

Innovative therapeutics for retroviral diseases will hopefully arise from a better understanding of how retroviruses reproduce in the cell, how they interact with host cell factors and how they subvert the host innate and adaptive immune systems. The early stages of the retroviral life cycle are particularly attractive therapeutic targets, but many of these steps are still poorly understood.

The life cycle of a retrovirus

The life cycle of a retrovirus

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The retroviral life cycle is arbitrarily divided into two phases, early and late. The stages in each phase are shown above. Interactions between viral and host cell factors occur at every stage of the viral life cycle, although many are still poorly understood. Identifying and understanding these interactions are key to developing new treatments to combat retroviral diseases. The steps inhibited by three retroviral restriction factors TRIM5alpha, APOBEC3G and Fv1 are also indicated. (RTC, reverse transcription complex; PIC, pre-integration complex)

One area of research in my lab is to investigate the link between XMRV and prostate cancer and CFS. We are also interested in the prevalence of the virus in the general population and the risk to human health. Our initial focus has been to set up serological assays for XMRV and test patient sera for antibodies to the virus. We can also screen for the presence of viral nucleic acid and proteins. In addition we are interested in the susceptibility of this virus to restriction factors in the host.

Examples of XMRV neutralisation activity in human serum

Examples of XMRV neutralisation activity in human serum

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Graphs show that the infectivity of XMRV is reduced after incubation with a subset of human serum or monoclonal antibodies raised to the envelope protein. Infectivity is plotted against the reciprocal dilution of the serum (black circles, left panel, subject Q488, right panel, subject Q610; blue triangles, negative control, monoclonal antibody 603; red squares, positive control, monoclonal antibody 83A25’). The dashed line indicates viral infectivity in the absence of sera. Subject Q321 shows strong neutralising activity whereas subject Q488 shows weaker neutralising activity.

We are also interested in defining the specific functions of viral and cellular proteins during the early post-entry steps of the retroviral life cycle. Initial studies are focusing on the p12 protein from the model retrovirus, murine leukaemia virus (MLV). p12 is formed when the Gag poly-protein is cleaved into individual proteins during viral maturation and it is essential for MLV replication. We aim to use p12 to study the components and localisation of the retroviral reverse transcription complex (RTC)/ preintegration complex (PIC), the kinetics of uncoating and trafficking, and the important interactions that occur between viral components and the cell. We will elucidate the function of p12 using a three-pronged approach. By combining virological assays with biochemical/biophysical techniques and microscopy, we hope to build up a picture of how p12 interacts with both viral and cellular factors, where p12 localises in the cell and at exactly what point(s) in the life cycle p12 function is important.

Retroviral Gag proteins and MLV-p12 mutants

Retroviral Gag proteins and MLV-p12 mutants

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All retroviruses encode a Gag polyprotein that is processed into at least three proteins, matrix (MA), capsid (CA) and nucleocapsid (NC), that form the structure of the virion. Most retroviruses also contain additional Gag cleavage products, for example, the p12 protein of MLV and the p6 protein of HIV-1. The full amino acid sequences of p12 from XMRV and Moloney-MLV are shown in grey, with residues that differ between them highlighted in black. The PPPY late domain motif is circled. The blocks of residues that when changed to alanines inhibit the early stages of the retroviral life cycle are shown below, together with the name of the mutant (adapted from Yuan et al, EMBO J. 1999). PM6 and PM8 (red) fail to reverse transcribe, while the remaining mutants arrest replication after cDNA synthesis but before integration.

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Bishop group

Dr Kate Bishop

Kate Bishop
kbishop@nimr.mrc.ac.uk

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