The molecular genetics of mammalian retroviruses and their interaction with their hosts

Lead Research Organisation: MRC National Inst for Medical Research

Abstract

A large fraction of the vertebrate genome comprises sequences encoding retroviruses. These elements are called endogenous retroviruses. Since these agents can cause harm it is important that vertebrates can control their own complement of viruses. One strategy to this end is the evolution of so-called restriction factors; natural proteins that can interfere with the replication of retroviruses. Efforts in the lab focus on a better understanding of retrovirus replication and how restriction factors might control the process. We are studying two genes, called Fv1 and Trim5, which are capable of protecting against retroviral infection. We are characterizing their distribution, specificity and mode of action. We hope that this study will give us both a better understanding of how retroviruses grow as well as suggesting alternative means of combating infection by retroviruses like HIV that cause fatal illness in humans.

Technical Summary

One key step in the retroviral life cycle that takes place in newly infected cells is the integration of newly synthesised retroviral DNA into the cell genome forming a provirus. This allows a permanent association to form between the viral and cellular DNAs; if the infected cell were a germ cell the proviral DNA can become a permanent part of the germ line. The novel provirus, or endogenous retrovirus (ERV), will show stable mendelian inheritance. Current estimates indicate that tens of thousands of these elements are present in the germ line of all vertebrates. Most appear to be silent passengers, but some can be expressed with a variety of consequences for their hosts. Study of the ERVs shows that retroviruses and their hosts have co-existed for tens of millions of years, implying that evolution of natural retrovirus restriction genes is likely. Using a range of molecular and virological techniques we are investigating two such restriction genes. First, we are characterizing a murine gene called Fv1 which acts to interfere with murine leukaemia virus (MLV) replication by preventing integration of viral DNA. Second, we study a primate gene called Trim5 which can prevent reverse transcription of both lentiviruses like HIV and gammaretroviruses like MLV. Fv1 appears to be derived from an endogenous retrovirus. To understand its mode of action, we are carrying out in vitro studies to examine the specificity of restriction, the nature of the interaction between restriction gene and its viral target, interactions with other cellular genes and the importance of the specific intracellular localisation of the Fv1 gene product. Similar studies are also underway with Trim5. One important finding in both systems has been that restriction involves an interaction between a multimeric restriction factor and polymerised viral capsid protein. This emphasizes a need to understand normal retroviral assembly/disassembly thereby prompting us to collaborate extensively with Dr Ian Taylor from the Molecular Structure Division of NIMR. It is hoped that understanding the mode of action of cellular restriction factors will shed light on the early steps in the retroviral life cycle and may ultimately suggest alternative means of interfering with retrovirus replication.

Publications

10 25 50
 
Description acre
Geographic Reach UK 
Policy Influence Type Participation in advisory committee
Impact Membership of ACRE (2002-2008) Advice to UK Gov on GM releases into environment
 
Description vectors
Geographic Reach UK 
Policy Influence Type Participation in advisory committee
Impact ad hoc advisor to SACGM on most appropriate classification of activities involving retroviral/lentiviral vectors. Revised guidelines issued.
 
Description xmrv
Geographic Reach Multiple continents/international 
Policy Influence Type Gave evidence to a government review
Impact advised UK-DOH nepnei, USA FDA bpac, Canadian PHA on risk of XMRV to blood supply
 
Description aog 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom 
Sector Public 
PI Contribution knowledge
Collaborator Contribution experimental/analysis
Impact 18286572 18714015 21131187
Start Year 2007
 
Description dl 
Organisation Technical University of Dresden
Country Germany 
Sector Academic/University 
PI Contribution virological analysis
Impact 18367529
Start Year 2007
 
Description it 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom 
Sector Public 
PI Contribution Biological/virological characterization of proteins
Collaborator Contribution Expertise protein biochemistry/structure determination
Impact 16873278 17493656 18222469 19007792 20833376 21483490 21436027
 
Description jc 
Organisation Tufts University
Country United States 
Sector Academic/University 
PI Contribution knowledge
Collaborator Contribution Analysis
Impact 17967065 19815721
 
Description th 
Organisation Northwestern University
Country United States 
Sector Academic/University 
PI Contribution Microscopical analysis
Collaborator Contribution analysis, discussion
Impact 17392513
Start Year 2006
 
Description ts 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom 
Sector Public 
PI Contribution biological/virogical definition of interaction
Collaborator Contribution mathematical modeliing
Impact 16912305 20833376
Start Year 2006