This article was originally posted on RealClearScience.
Viruses are pernicious beasts. Some of them can sneakily hide inside the body, long after the initial infection has been cleared. For instance, varicella zoster virus (VZV), a type of herpesvirus that causes chickenpox, survives in an inactive state inside nerve cells for the remainder of a person’s life. Then, for unknown reasons, it can reactivate, causing shingles in old people or even healthy 30-year-olds. Other viruses may play a role in chronic conditions such as asthma or inflammatory bowel disease.
For these reasons, knowing the viruses to which a patient has been exposed throughout his life can provide useful insights for both diagnostic and research purposes. But given both practical and technological limitations, there was no good way to perform such a test. Now, an international team of researchers, based mostly out of Harvard, has invented a device that can conduct a large-scale screen of prior viral infections. And amazingly, all that is required is a single drop of blood.
How It Works
The new platform, which the team calls VirScan, is based on a well-known technique called phage display. This clever technique examines protein-protein interactions. In this case, the team is interested in knowing if antibodies from a patient’s blood sample bind to proteins from human viruses. If at some point in the past a patient was infected with a particular virus, his blood should contain antibodies against proteins from that virus.
The researchers created an enormous “library” of nearly 94,000 protein sequences from every virus that infects humans. In total, they retrieved protein sequences for more than 1,000 different strains representing 206 viral species. From the protein sequences, they deduced the DNA sequences which encoded them. Then, they synthesized short DNA segments (200 “letters” long) based on these sequences and cloned them into T7 phage, small viruses that infect only bacteria. When grown, the phage “displayed” on their surfaces the small proteins encoded by the short DNA segments. In other words, the phage were acting like mannequins, except instead of clothing, they were displaying small human virus proteins. (See figure below, panels a-c).
Next, the authors combined the phage with antibodies (panel d) extracted from human blood. If the blood sample contained antibodies against any of the proteins displayed on the phage particles, they would bind. Then, special antibody-binding proteins with tiny magnetic beads attached were added to the mixture (panel e). This allowed the phage with antibodies attached to be isolated, while the phage without antibodies attached were washed away and discarded. Thus, only phage displaying virus proteins that had been bound by an antibody were kept. By amplifying and sequencing the short DNA segments inside these phage (panel f), the researchers could determine against which viruses the individual had developed antibodies.
Patients’ Viral Histories
Using their new tool, the researchers examined blood samples from 569 people. They found that the average person has been infected with 10 viral species. (See graph.)
Ten viral species may seem rather low. Considering that adults catch between two and four colds per year, it might be expected that the average person would be exposed to far more than ten viral species. However, a person can become sick if exposed to different strains of the same species of virus. There are many different strains of rhinovirus, for instance, which is the most common cause of colds. So, a person who had twenty infections with twenty different strains of rhinovirus would still only register as having been infected by one viral species. Interestingly, two of the individuals had been exposed to 84 viral species. (It is unclear if those individuals were Gene Simmons, Ron Jeremy, or Charlie Sheen.)
Excluding volunteers with HIV and HCV, the authors created a list of the most common viruses. (See chart; the number represents the percentage of individuals who tested positive for the virus.)
Of the top five most common viruses detected in their samples, four are causes of the common cold (rhinovirus A and B, adenovirus C, and respiratory syncytial virus), while human herpesvirus 4 is the cause of mononucleosis, the “kissing disease.”
Like every new technology, there are limitations. Probably the most serious drawback for VirScan is that the immune response wanes over time. Therefore, VirScan would give false negatives for any viruses against which a person’s immune system is no longer producing antibodies. However, in an interview with RealClearScience, principal investigator Dr. Stephen Elledge suggested a possible solution: Activate memory B cells, which “remember” previous infections, to produce antibodies. This should, in theory, solve the problem.
Additionally, Dr. Elledge’s team suggests that VirScan could be adapted to detect other microbes, such as bacteria, fungi, and parasites. At an estimated cost of merely $25, VirScan appears to represent a giant leap forward for personalized medicine.
Source: George J. Xu et al. “Comprehensive serological profiling of human populations using a synthetic human virome.” Science 348 (6239). 5-June-2015. doi: 10.1126/science.aaa0698