Viruses known as retroviruses integrate into the genetic material of those they infect. This ability may change the traits of the infected, in sickness and in health
All viruses are parasites that use the host cell to replicate their genome. Retroviruses are one family of viruses, which also integrate a copy of their genome into the genome of the host cell. During evolution, viral genes integrated into the human genome, as well as the genomes of other mammals, and were preserved for millions of years. Some are involved in disease processes, some are inactive, and some are even beneficial. Recently, it was found that some of those same viral genes are related to the development of different diseases—including cancer and degenerative diseases of the nervous system (neurodegenerative diseases).
Retroviruses integrate a copy of their genome into the host cell. Illustration of a retrovirus infecting a cell and inserting its own genetic material into it | Gregoire Cirade, Science Photo Library
What are retroviruses
One of the main roles of our body’s cells is to produce proteins. Our genetic material, or DNA, is packed into the nucleus of each and every cell; it contains instructions for the production of all the proteins in our body. The DNA is used as a template to produce RNA—a similar molecule that dictates the production of the protein. When a virus infects a cell, it takes over the systems of the host cell and enslaves them to replicate itself.
The genetic material of RNA viruses is RNA—in other words, they contain the genetic material that can be translated directly to a protein without using a DNA template. The genetic material of retroviruses is also RNA, but they belong to a different family of viruses and their replication process is different to that of RNA viruses: instead of using RNA directly to replicate themselves, the genetic material they insert into the host cell leads to the production of an enzyme that can assemble DNA according to an RNA template, in a process known as reverse transcription. Subsequently, the DNA produced by this process is integrated into the host genome, and thus the virus can remain permanently in the host cell and cause it to produce more and more copies of itself. If the virus infects a reproductive cell—an egg cell or a sperm cell—it can be inherited by future generations. Thus, many viral genes have entered our genome and those of other animals, including other primates, turtles, bats, and rabbits, and have been preserved throughout evolution. Some viruses from the retrovirus family cause diseases in humans, including HIV, which causes acquired immunodeficiency syndrome (AIDS), while other viruses in this family are not known to be disease vectors.
Some viruses from the retrovirus family cause diseases in humans, such as HIV. Illustration of the process of infection of a cell by the virus | NIAID, Science Photo Library
Retroviruses have benefits
The human genome carries the signs of our evolutionary journey over the years. Among these signs we can find remnants of ancient viral infections that infected our forefathers millions of years ago. These remnants are called HERV—human endogenous retroviruses; they comprise about 8% of the genome in our cells. Often, retroviruses that enter our cells lose their ability to create infectious copies, due to errors—mutations—that take place in their DNA sequence. If such damaged viruses are “trapped” in the DNA of a reproductive cell and are inherited by future generations, they are considered endogenous to the human body, in other words, an integral part of it.
Because of mutations in the integrated sequence, most of the viruses originating in HERV no longer lead to the production of proteins. For this reason, for many years researchers believed that they played no role, and they were considered “junk DNA”. Recently it was discovered that some of them are still responsible for building viral proteins involved in biological processes essential for our body, and some may even affect our health and the development of diseases.
In the Human Genome Project, scientists sequenced all of the human DNA and found about 500 genes originating in retroviruses responsible for producing envelope proteins—proteins that envelop the virus, and among other things, enable it to infect cells. Among these 500 genes, 16 genes act permanently in healthy tissues, including the testicles, placenta, and thyroid gland. Three of them are particularly active in the placenta. Originally, the HERV viruses used the proteins produced by these genes to connect the viral particles to the host cell and fuse to the cell membrane, in order to enter the cell and infect it. These proteins also defended the viruses from the immune system and protected them from it during infection. Protection from the immune system may be advantageous during fetal and placental development; the new fetus must be protected from the mother’s immune system in order to continue growing. Today, we know that these genes, known as syncytins, are involved in the production of a protective membrane around the fetus that allows it to attach to the uterine membrane and protects it from the mother’s immune system. During human evolution these viral genes appear to have been beneficial, and over the course of time became human genes in every way.
Genes originating in retroviruses are involved in the production of a protective layer around the fetus. Illustration of fetus and placenta | Shutterstock, SciePro
Genes from HERV that lead to the production of envelope proteins may give the host body protection against infection by other viruses. Some of these envelope proteins are known to block the entry of similar viruses into the cells. After a virus infects a cell it replicates itself to produce many new viruses, which leave the cell. The objective of these viruses is to enter neighboring cells and infect them, while skipping over already infected cells. The viruses do this through several mechanisms, not all of which are well-known to science, and many of which are being studied intensively. The mechanisms known to us today include, for example, preventing entry into an infected cell by blocking the cell’s receptors or by removing the receptors from the cell’s surface—similar to the HIV mechanism.
Certain HERV genes are responsible for producing proteins that may lead to the development of various diseases. Electron microscope photo of HERV viruses | Photo: Dr. Klaus Boller, Science Photo Library
Involvement in diseases
Studies have shown that certain HERV genes are responsible for the production of proteins that may lead to the development of various diseases, such as certain types of cancer and neurodegenerative diseases, and may also affect fetal development and aging. The number of HERV genes and their location in the genome differ from person to person; these differences may be linked to the appearance of various diseases. Differences in the activity of HERV genes between men and women, and among different populations of humans around the world, have also been found..
Some viruses are known to cause cancer. Infection by the papillomavirus, for example, may cause cervical cancer, anal cancer, penile cancer, or throat cancer; while chronic infection by hepatitis B and C viruses may cause liver cancer. But the HERV story is different. It’s a story of viral gene remnants that are part of our genome, rather than a new infection from outside. One of the studies published on this issue proposed that the expression of genes of HERV of type K (HERV-K) causes inhibition of the immune response and impacts its effectiveness, thus contributing to the progression of testicular cancer. The effect of HERV on cancer is still being studied, but it appears that uncontrolled expression of its genes may lead to different types of cancer.
But it’s not just about cancer. Scientists from Maryland in the USA found a relationship between HERV genes and the development of different neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS). They found that some ALS patients express a HERV-K gene that is not expressed in healthy people. The scientists initiated production of the viral protein in a culture of human-derived brain cells and found that it caused them to degenerate. The scientists then used genetic engineering to cause mice to produce the protein, and as a result the mice developed symptoms of the disease.
Multiple sclerosis is an autoimmune disease in which immune cells attack the myelin, the isolating layer around nerve axons in the brain. As a result, the electric signals are not transferred correctly, leading to pain, muscle weakness, and damage to thinking and memory skills. Multiple sclerosis, which is also considered a neurodegenerative disease, has been found to be related to the expression of HERV genes. As early as 1991, scientists managed to isolate viral DNA from multiple sclerosis patients and linked it to a virus that was named the multiple sclerosis-associated retrovirus. Ten years passed before they discovered that this virus actually belongs to the HERV-K family.
Different studies have shown that the main cause of the emergence of multiple sclerosis is infection by Epstein-Barr virus (EBV), which belongs to the herpes virus family and causes glandular fever. In a study published in Immunity, it was found that Epstein-Barr virus activates a HERV-K gene that leads to the production of a superantigen—a protein that produces a severe multi-systemic inflammatory response that takes place in some glandular fever patients. Production of superantigens by HERV may also explain its involvement in various autoimmune diseases, such as type 1 diabetes, in which the body destroys the cells that produce insulin. Two additional autoimmune diseases, rheumatoid arthritis and lupus, have also been found to be related to the expression of HERV genes that are similar to human genes, such that the body mistakenly identifies the human genes as harmful and attacks them.
Schizophrenia is a chronic mental illness characterized by thinking, perception, emotional, and behavioral disorders. A paper that reviewed the genome sequence and expression of proteins in people with schizophrenia claimed that the emergence of the disease may also be linked to the expression of HERV genes in some of the people. Other HERV genes may also affect bipolar disorder: studies have shown that genetic factors that raise the risk of schizophrenia are also linked to the emergence of this disease. Nevertheless, very few studies have been conducted on the relationship between schizophrenia and HERV, and those that were conducted were very small and examined few patients. If in the future, enough large, good studies are conducted to prove the causal relationship between these mental illnesses and the expression of HERV genes, we may perhaps be able to develop new therapies for those diseases that inhibit the activity of the genes responsible for them, or inhibit the proteins produced by the genes.
Scientists found a link between HERV genes and the development of various neurodegenerative diseases. Illustration of the involvement of HERV proteins in ALS (right) and multiple sclerosis (left) | Nicolle R. Fuller, Science Photo Library
HERV as a therapeutic target
Antibody-based drugs for the treatment of different types of cancer already exist today. Some of the antibodies inhibit cell division to prevent the tumor from growing further, some activate the immune system and direct it at the tumor and some inhibit the production of new blood vessels that nourish the tumor. In light of the findings proving that HERV genes are involved in the development of cancer, these genes have become a further target of disease treatment.
In 2012, scientists from Texas found that one of the genes from the HERV-K family is particularly active in breast cancers, and used mice to determine whether the protein produced could be used as a target for treating such tumors. They found that antibodies for this protein improve the state of the mice and inhibit the development of the tumor. In a study published recently in Nature, the researchers found antibodies for HERV proteins that facilitated the treatment of lung cancer in mice. In an interview for the British newspaper, Guardian, George Kassiotis, who led the research, said that the results of the study may lead to future development of a new treatment for lung cancer, perhaps even in the form of a vaccine comprising HERV proteins that encourage the production of antibodies.
Technological advancement has enabled researchers around the world to analyze a large, complex database originating from endogenous retroviruses, which was obtained by sequencing human DNA. However, there are still more questions than answers. Further studies are needed to better understand the role of these genes in various diseases. The hope is that this information will allow us to develop effective treatments for these diseases by shutting down or activating the ancient retroviruses remnants that penetrated the human genome and now comprise 8% of it. It is already clear today that retroviruses, which integrated into our genetic material and became part of it, have had an impact on us: for better and even for worse.
Hank Green from SciShow explains how retroviruses have affected our evolution: