While many of the world’s most dangerous diseases are caused by viruses, not all viruses pose a threat to human health. In fact, many are beneficial, and can be used to prevent or treat diseases.
What is a virus?
Viruses are peculiar little things. Typically many times smaller than a bacterial cell, a virus particle (also known as a virion) consists of an infectious bundle of nucleic acid (DNA and/or RNA) surrounded by a protective protein coat called a capsid. The capsid is composed of many identical protein subunits, known as capsomeres. Some viruses also have an outer layer, known as the viral envelope, which is typically derived from the cell membrane components of infected hosts, such as phospholipids and proteins. Anyone looking for a free, comprehensive introduction to virology would do well to check out Prof. Vincent Racaniello’s virology blog, where you can find the entire course materials for his undergraduate virology course at Columbia University: including lecture slides, study questions, extra reading and video recordings of all lectures.
Living or Non-living? Good or Bad?
Despite a recent bold attempt to incorporate viruses into the universal tree of life on the basis of a data-driven phylogenomic study (Nasir and Caetano-Anollés, 2015), the consensus within the scientific community is that viruses are non-living entities. Alive or not, most people assume that viruses are only good for one thing: causing disease – be it a common cold, leading only to mild sniffling and sneezing, or a rampant pandemic cutting a swathe through vast regions of the globe. While there is ample evidence as to why many viruses deserve their ‘bad rap’ (Ebola virus and Zika virus being contemporary examples), other viruses can play a positive role for humanity and/or life as a whole.
The production of effective vaccines, which can be administered to protect human populations from infectious viral diseases, is perhaps the most obvious way by which our understanding of viruses – and often the viruses themselves – can be beneficial to humanity. Ever since 1796 – when Edward Jenner first postulated that people who had been previously infected with cowpox virus were protected from infection with the smallpox virus (Riedel, 2005) – viruses have been recruited by humans to prevent serious viral infections. There are several ways by which this can be achieved. One example is the generation and administration of ‘live attenuated’ vaccines, whereby a patient is administered with a strain of virus which has been altered in such a way as to make it less virulent. Due to the fact that vaccine strains are not virulent enough to cause an actual infection, this is a safe method by which to train a person’s immune system to recognize the viral antigens, and hence to protect against infection by the more virulent strain(s). Another approach is to purify one or more viral antigens and administer them in the absence of whole virus particles. Again, this method acts to safely train the immune system to recognize these antigens and to protect against infection (Rhee, 2014).
When a large percentage of a population has become immune to infection by a particular pathogen – for example, through natural exposure or vaccination – susceptible individuals are also better protected. This phenomenon is known as ‘herd immunity’.
The replication cycle of retroviruses, such as human immunodeficiency virus (HIV), involves the integration of viral DNA into the host’s genome (Roossinck, 2011). Although many retroviruses are known to cause acute illnesses, virtually all eukaryotes – including humans – are asymptomatic carriers of so-called endogenous retroviruses (ERVs). These are regions of DNA which appear to have been derived from the previous integration of retroviruses into the host genome, but which are typically no longer capable of causing an illness. An estimated 8% of the human genome is derived from retroviral DNA, and these ERVs are conserved across non-human primates – indicating that the endogenisation events leading to their creation occurred long ago. In other words, an ERV carried in the genome of a parent can be inherited by its offspring, then passed down to the offspring’s offspring, and so on. No one knows the exact reason why these endogenisation events occurred (Roossinck, 2011). However, it is hypothesised that each one occurred as a survival method, in response to a ‘plague-culling’ event (i.e. the initial aggressive period in which infection of humans with a retrovirus leads to widespread sickness and death – this is typically followed by the establishment of a commensal or even mutualistic symbiotic relationship between the surviving humans and the retrovirus). For example, endogenisation may occur as a response to the presence of an otherwise lethal virus, immunising individuals who carry the endogenised retrovirus (Roossinck, 2011). This hypothesis is supported by a retrovirus endogenisation event identified in koalas. Koala retrovirus (KoRV) is the causative agent of koala immune deficiency syndrome (KIDS), which – in a manner akin to acquired immune deficiency syndrome (AIDS) in humans – increases an individual’s risk of acquiring infectious diseases and/or developing cancer. Koalas from the northern Australian mainland harbour the endogenised, attenuated version of KoRV and are therefore immune to infection with the virus. However, koalas living off the south coast, on Australia’s third-largest island, Kangaroo Island, do not harbour this endogenised KoRV and are therefore susceptible to acute infection with KoRV (Roossinck, 2011).
An attenuated, endogenous form of koala retrovirus which has been previously integrated into the genome of a koala can protect the individual from infection with the debilitating virus.
Harnessing the destructive nature of pathogenic viruses, and using it to our advantage, may soon become a key strategy in the fight against one of the biggest current threats to human health – cancer. An ideal anticancer therapy should specifically target and kill tumour cells, leaving healthy cells largely unharmed. However, traditional anticancer treatments such as radiotherapy and chemotherapy are associated with various limitations, such as chemoresistance, radioresistance and cytotoxicity towards healthy cells (Badrinath et al., 2016). Recent advances in genetic manipulation have enabled the development of genetically-engineered viruses with a view to their use as anticancer therapeutics. Given that pathogenic viruses naturally lyse infected cells and stimulate the immune system to attack these cells also, being able to specifically target these effects to tumour cells may prove invaluable.
Virotherapy – that is, the act of recruiting and reprogramming viruses to treat disease – has a surprisingly rich history. The earliest known clinical trial of a virotherapy was carried out way back in 1949, and involved 22 patients suffering from Hodgkin’s lymphoma. The participants were administered several sera/tissue extracts containing what was referred to as ‘hepatitis virus’ (likely Hepatitis B), on the basis of the fact that the contraction of viral hepatitis was thought to be correlated with remission. The results were mixed: some patients exhibited limited improvements, while an undisclosed number of patients lost their lives – either due to the cancer, or as a direct result of the treatment (Kelly and Russell, 2007).
Now, more than 65 years later, researchers can manipulate viruses in numerous ways to promote the specific targeting of tumours, either by making the viruses less capable of infecting normal cells, or hindering them in such a way that they are only able to replicate in- and cause damage to tumour cells – leading to a tumour-targeted immune response (Badrinath et al., 2016). In 2015, a genetically-engineered herpes virus known as T-Vec was approved by the FDA for the treatment of inoperable melanomas. (The treatment was approved in Europe in January 2016.) The altered T-Vec herpes virus can invade both cancerous and healthy cells, but it cannot replicate in healthy cells because it lacks an important protein. In theory, then, cancerous cells should be selectively targeted and destroyed. Another example of a recently-developed virotherapy is the genetically-engineered adenovirus H101, which was approved in China in 2005, as a treatment for head and neck cancer (Badrinath et al., 2016). With many more promising viruses in the pipeline, virotherapy may soon come to the forefront as an alternative treatment for cancer patients.
With the emergence of virus-based anticancer therapies and gene therapies, vaccines are no longer the only beneficial application of viruses in human health.
The use of virotherapy to treat cancer is just one aspect of an even bigger field of research known as gene therapy. Gene therapy involves the use of nucleic acids (DNA and/or RNA) for the treatment or prevention of genetic disorders (Kaufmann et al., 2013). Depending on the type of disease, this can be accomplished either by delivery of a functional, therapeutic gene as a substitute for the defective or missing endogenous counterpart, or by reducing the levels of a harmful product produced from a defective gene (Kaufmann et al., 2013).
In order for gene therapy to work, the therapeutic nucleic acids need to be delivered successfully to a patient’s target cells. Some viruses, such as retroviruses and adenoviruses are prime delivery vectors, as they have already been proven to be capable of invading human cells and reprogramming cellular processes (Kaufmann et al., 2013).
It is clear that viruses are capable of contributing positively to human and animal health, be it through natural means, such as in the koala story, or as genetically-engineered anti-tumour weapons, or vectors for gene therapy. While the concept of using viruses as therapeutic agents may still be a relatively new one, the potential advantages are many, and it would no doubt be of great benefit for us to pursue these treatments further.
- Nasir, A., Caetano-Anollés, G. (2015) A phylogenomic data-driven exploration of viral origins and evolution. Science Advances. 1(8), e1500527.
- Riedel, S. (2005) Edward Jenner and the history of smallpox and vaccination. Proceedings (Baylor University Medical Center). 18(1), 21–25.
- Rhee, J.H. (2014) Towards vaccine 3.0: new era opened in vaccine research and industry. Clinical and Experimental Vaccine Research. 3(1), 1-4.
- Roossinck, M.J. (2011) The good viruses: viral mutualistic symbioses. Nature Reviews Microbiology. 9(2), 99-108.
- Badrinath, N., Heo, J. and Yoo, S.Y. (2016) Viruses as nanomedicine for cancer. International Journal of Nanomedicine. 11, 4835-4847
- Kelly, E. and Russell, S.J. (2007) History of oncolytic viruses: genesis to genetic engineering. Molecular Therapy. 15, 651-660.
- Kaufmann, K.B., Buning, H., Galy, A., Schambach, A. and Grez, M. (2013) Gene therapy on the move. EMBO Molecular Medicine. 5, 1642-61.