Mapping the up-regulation of Human Endogenous Retrovirus K with respect to the development of cancer and other diseases

Lead Research Organisation: University of Oxford
Department Name: Zoology

Abstract

The deciphering of the human genome in 2001 revealed that around 8% resembles viral genes, suggesting a viral origin. Subsequent deciphering of animal genomes has shown that viruses have been invading and colonizing genomes for millions of years. We call these viruses, which reside within our genomes, endogenous retroviruses (ERVs). While there are many studies connecting ERVs with disease in animals, in humans no definitive link has been demonstrated, although recently an ancient ERV was connected with Hodgkins lymphoma, a cancer of the immune system.

I propose to study the most recently active ERV within the human genome, namely HERV-K HML-2 (HK2), with respect to its expression during the development of human disease, focusing on cancer.

Why focus on HK2? We know that ERVs are strongly connected with their host. Their efficiency in colonizing host genomes is better when the viral infection is milder. A simple example demonstrates this principle: if a virus kills the host by infection then it commits suicide by destroying its "colony" as well. My recent study has shown that ERVs colonize genomes more efficiently when they lose their ability to move between different cells and individuals. Therefore, my recent study suggests that ERVs, which were transformed to use within cell life-cycle apart from being stealth to antiviral responses, they are also milder and more friendly to their host. On the other hand, viruses that have not adapted by changing their life-cycle, are expected to be more pathogenic. HK2 belongs to this kind of potentially pathogenic ERVs.

I will firstly develop a robust laboratory framework and describe the intensity of the HK2 expression in a large sample of patients (with cancer or HIV infections) and healthy volunteers. This will allow me to study the history of HK2 expression throughout the development of diseases. Finally, I will study if HK2 is spreading between cells of the same patient as a result of its up-regulation, to determine whether it could also be infectious and transmitted to other people as well.

The project will engage as collaborators researchers working on cancer epidemiology, HIV and other retroviruses and immunologists from the Universities of Oxford, Harvard, Athens and Imperial College. A large biobank with more than 100,000 samples deeply frozen and collected since 1990 will contribute the majority of the required 800 samples. The project is expected to have an impact in understanding cancer and its development, but also it could prove to be of high importance for transfusion and blood product safety.

Technical Summary

Endogenous retroviruses (ERVs) differ from typical retroviruses in being inherited through the host germline and are therefore a unique combination of pathogen and selfish genetic element. Around 8% of the human genome is comprised of human ERVs (HERVs), most of which ceased replicating at least 5 million years ago. The most notable exception is the HERV-K HML-2 (HK2) lineage. Recent studies have shown that, although HERVs are replication defective and/or transcription-translation silenced in healthy subjects, in some patients (e.g. breast cancer, HIV infected, inflammatory disease) HK2 loci have been up-regulated and produce detectable viral titers in the plasma. My project will investigate: a) the disease spectrum of up-regulated HK2, b) the timeline of HK2 up-regulation compared to the timeline of the disease development and c) the infectious potential of the up-regulated HK2 loci.

Why focus on HK2? My recent study suggests that ERVs are more efficient parasites to replicate within the genomes when they lose their env gene and, thus, change their life-cycle into facultative intracellular. This also suggests that env-less ERVs could be less pathogenic. HK2 however is the most recent lineage with conserved env genes. Thus, it is less likely to be well-adapted and might still carry pathogenic traits for its host.

The project will follow an integrated epidemiological and experimental design split into 4 phases: a) development of robust experimental framework to study HERV up-regulation with respect to human disease, b) cross-sectional study of HK2 up-regulation with respect to disease spectrum, c) longitudinal retrospective case-control study of HK2 up-regulation and d) in depth analysis of within patient dynamics of HK2.

A team of collaborators in the fields of cancer, retroviral infections and immunology from the Universities of Oxford, Harvard, Athens and Imperial College will support the successful implementation of the project.

Planned Impact

Application: Identifying populations at risk of developing cancer
Beneficiaries: General population, policy makers of cancer preventions programs
HK2 load could be proven a marker of susceptibility to developing cancer. If this is proven to be the case, then a simple test could help allocate preventive medicine interventions (e.g. pre-symptomatic screening) in higher risk populations.

Application: Development of cancer therapeutics and imaging
Beneficiaries: Cancer patients
If the HERV-K load is connected with cancer intensity or stage then it could be used as a biomarker in treatment follow-up in cancer patients (e.g. post operative adjunct chemotherapy, number of additional chemotherapy cycles etc). Finally, as previously said in the Academic Beneficiaries section, other groups are already working on the development of immunotherapies based on HERV-K. The project's results will boost the probability of getting these approaches into the application stage.

Application: Blood products and transfusion safety
Beneficiaries: Transfused patients
If HERV-K is found to be infectious within a patient, then the probability of transmission between individuals should be explored, too. Blood transfusions should be the first area that needs to be explored to identify if a patient developed HK2 viral load after getting transfused with blood or blood product with detectable HK2 viral load.
Finally, since HK2 could be a more sensitive marker of early HIV infection than HIV antibody test or HIV nucleic acid test, the probability of screening blood products in high HIV prevalence areas (e.g. South Africa) using a cheaper HK2 load approach could prove to be a cost-efficient strategy.

The timescale for the previously mentioned beneficiaries is expected to be around 5-10 years after the beginning of the project and will largely depend on the necessity of confirmatory follow-up studies (e.g. larger multi-center studies).

Publications

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Friedman SR (2014) Socially-integrated transdisciplinary HIV prevention. in AIDS and behavior

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Gray RR (2013) Evolutionary analysis of hepatitis C virus gene sequences from 1953. in Philosophical transactions of the Royal Society of London. Series B, Biological sciences

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Hurst TP (2015) Activation of the innate immune response by endogenous retroviruses. in The Journal of general virology

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Karamitros T (2018) Human Endogenous Retrovirus-K HML-2 integration within is associated with intravenous drug abuse and modulates transcription in a cell-line model. in Proceedings of the National Academy of Sciences of the United States of America

 
Description Viral Hepatitis-A Very Real Consequence of Substance Use
Geographic Reach North America 
Policy Influence Type Citation in other policy documents
URL http://www.drugabuse.gov/related-topics/viral-hepatitis-very-real-consequence-substance-use
 
Description BRC Cancer Sequencing
Amount £10,000 (GBP)
Organisation Oxford University Hospitals NHS Foundation Trust 
Department NIHR Oxford Biomedical Research Centre
Sector Public
Country United Kingdom
Start 01/2014 
 
Description CONICYT Scholarship
Amount £110,000 (GBP)
Organisation National Commission for Scientific and Technological Research (CONICYT) 
Sector Public
Country Chile
Start 10/2014 
End 09/2018
 
Description Clarendon Fund
Amount £100,000 (GBP)
Organisation University of Oxford 
Department Clarendon Fund
Sector Academic/University
Country United Kingdom
Start 10/2014 
End 09/2017
 
Description Collaboration with National Development Research Institutes 
Organisation National Development and Research Institutes
Country United States 
Sector Charity/Non Profit 
PI Contribution We provide expertise in molecular phylogenetics and virology.
Collaborator Contribution They provide expertise on interventions in Persons Who Inject Drugs.
Impact Multidisciplinary collaboration: 1) Social Scientists, 2) Virologists, 3) Biologists
Start Year 2017
 
Description Collaboration with National Retrovirus Reference Centre Biobank 
Organisation National and Kapodistrian University of Athens
Country Greece 
Sector Academic/University 
PI Contribution We will be analysing biological samples provided by the databank.
Collaborator Contribution The partners will be provided biological samples.
Impact No outputs for the time being. Data are still analysed.
Start Year 2013
 
Description Collaboration with University of Miami 
Organisation University of Miami
Country United States 
Sector Academic/University 
PI Contribution We will be sequencing the genomes of ocular melanoma and germline samples
Collaborator Contribution The partners provide genomic DNA from ocular melanoma and matched germlines.
Impact No data. Analyses still active.
Start Year 2014
 
Description Genomics England Clinical Interprentation Partnership (GeCIP) domain for Genomics England 
Organisation Genomics England
Country United Kingdom 
Sector Public 
PI Contribution I have organised and co-lead the Functional Cross-Cutting GeCIP domain.
Collaborator Contribution Genomics England will provide us access to 100,000 genomes.
Impact We do not have any outcomes for the time being. We hope that soon by having access to the genomes we will be able to have results.
Start Year 2015