Integration of retrovirus DNA

Scientists in the Department of Veterinary Medicine are studying viruses as pathogens in host populations, endeavouring to understand the implications of our shared evolutionary history.

Perhaps one of the most unexpected findings has been the discovery of the degree to which viruses have been an evolutionary force.

When Charles Darwin’s On the Origin of Species went to press in 1859, viruses had yet to be discovered – it would be another 40 years after publication before the ‘concept of viruses’ was proposed, and a century later before breakthroughs in viral research would provide a clear understanding of their genetic make-up, how they replicate and how they cause disease. Perhaps one of the most unexpected findings has been the discovery of the degree to which viruses have been an evolutionary force, as witnessed by the accumulating genetic and immunological evidence of the ancient battles between viruses and their hosts. Scientists in the Laboratory of Viral Zoonotics led by Professor Jonathan Heeney are asking key questions about the evolution of viral pathogens by studying the transmission of viruses from animals to humans.

Epizootics and zoonotics

Human epidemics caused by highly contagious acute infections such as influenza and severe acute respiratory syndrome (SARS) loom foremost in our minds when we think of the large-scale transmission of viruses that have the capacity to cause high morbidity and mortality. But some of the more insidious viral infections may have a much greater impact on global health because, in the early stages, they cause subclinical infections, with the disease developing slowly and sometimes going unnoticed for many years. Human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) are examples that have caused relatively silent epidemics, in some cases infecting hundreds of millions globally.

Epidemics are not confined to humans. Not only have we witnessed animal epidemics (epizootics) that all too recently have circulated through our domestic livestock (foot and mouth disease, classic swine fever and bluetongue), but animal viruses can also be transmitted to humans under a variety of conditions. Recent examples of this type of zoonotic transfer include the pig-to-human transmission of swine flu virus and the bird-to-human transmission of avian flu virus, both of which have raised global concerns regarding new human flu pandemics.

How do these viruses evolve to enable them to cross between species? What complex series of events is required for the virus to infect humans and sustain infections at sufficient levels in a new species to become readily transmissible within a new population? Why are some individuals protected from developing full-blown disease despite being infected? These are the sorts of question that interest scientists in the Laboratory of Viral Zoonotics. This line of research involves the application of new molecular technologies to address aspects of zoonotic infections of importance to both veterinary and human health.

Fossils of ancient virological battles

Of particular interest to the team is a family of viruses known as the retroviruses, so named because of the ‘reverse’ way they reproduce themselves. Once a retrovirus has infected a cell, its RNA genome is replicated, or ‘reverse transcribed’, into DNA. This becomes integrated into the genome of the infected cell, so that it is copied every time the infected cell divides. Such integration explains why some viral infections such as HIV (the cause of AIDS) or human T-lymphotrophic virus (the cause of T-cell leukaemia or encephalopathies) are, in essence, persistent life-long infections.

Sequencing of the human genome has revealed that retroviral integration has in fact been ongoing for millions of years. Human genomes, and those of other mammals, are littered with retrovirus-like elements as remnants of virus integration. Fortunately, most have become defective and are no longer replication competent, and are often considered by others as junk DNA. Professor Heeney considers them as ‘viral fossils’.

Evolution of resistance

As a consequence of the thousands of years of battle between host and virus, our bodies have evolved many mechanisms to block or cripple those viruses that have the potential to threaten the survival of species. Understanding these processes and how hosts have evolved such viral defences may provide new insight into the co-evolution of species and viruses.

One area of research in Professor Heeney’s lab is the study of the recent ancestor of HIV, the simian immunodeficiency virus (SIV). Of particular interest is the elucidation of how SIV evolved from being a virus of non-human primates to being a new pathogen of humans, and how previous animal hosts developed mechanisms of disease resistance. Humans show a spectrum of disease progression following HIV infection, with some individuals being highly susceptible to infection, while others have increased resistance. Research in Professor Heeney’s lab is analysing how different natural African primate hosts have developed a relative resistance to AIDS-like diseases caused by these viruses. The data suggest that the animals have evolved mechanisms to control immune activation caused by new viral pathogens.

Another line of investigation is focused on how intrinsic host restriction factors (cell factors that can block or impair a stage of the viral life cycle) in a variety of non-human primates have influenced the evolution of different SIV viruses. At one stage in this evolutionary process, a subtype of SIV was transmitted from chimpanzees to humans, giving rise to the subtype of HIV-1 that has become the globally distributed human pathogen that causes AIDS. Understanding how pathogens have been kept under check in certain species, and how these species have undergone selection and developed resistance, will provide important insight into new treatments for other threatened species.

Understanding the good, the bad and the ugly

Linked to this area, a major effort in the lab is focused on identifying new types of virus that have adapted so well to their hosts that they have gone unnoticed under normal circumstances in healthy individuals. These viral infections may circulate within the human population without causing overt disease yet, subclinically, influence our daily health and wellbeing; moreover, if associated with other infections, such as those that cause hepatitis, these viruses may accelerate or alter the course of the disease. One project in the lab is investigating a highly contagious norovirus (a variant of the virus that causes winter vomiting disease in humans) that is completely asymptomatic in normal healthy mice but only rears its head and causes disease when the mouse genome loses particular genes responsible for natural antiviral responses. It is hoped that studies such as these will shed light on where disease outbreaks come from and how they persist.

Developing vaccines

The expectation is that lessons can be learned from understanding features of the long and intimate evolutionary history shared by mammals and retroviruses. Much of the knowledge of protective host responses to viral infection that is being uncovered in Professor Heeney’s group is being translated into the development of vaccines to combat complex persistent RNA viral infections such as HIV and HCV. Working with teams in London and Lausanne, the first early clinical trials have recently been completed, and subsequent trials to optimise immunity and delivery are being planned. New vaccine candidates are also in development and the outcome of their use for the containment of rapidly evolving blood-borne pathogens such as HIV and HCV is being actively studied.

For more information, please contact Professor Jonathan Heeney ( at the Department of Veterinary Medicine. Professor Heeney’s research is funded by the US National Institutes of Health and the Bill & Melinda Gates Foundation; a number of students and fellows in his laboratory are supported by the Wellcome Trust.


Cambridge Infectious Disease

Cambridge Infectious Disease (CID) is a Cambridge-wide initiative to bring together diverse groups studying aspects of infectious diseases, with the aim of coordinating the University’s commitment to tackling global health challenges imposed by infectious diseases of animals and humans. Many internationally recognised research groups spread across departments and disciplines in Cambridge are working in this area. By building capacity in infectious disease research and teaching, and by attracting new research partnerships and funding, the goal of CID is to amplify Cambridge’s impact on human and animal health worldwide.

In the spirit of commemorating Darwin, CID has this year chosen the theme ‘Infectious Diseases and Evolution’ for a meeting to be held on 22–23 October 2009; further details will be posted on the CID website.

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