Are the silent viruses within us doing more than we know?
By Laura Kasman, as told to Veronique GreenwoodIn the 1970s, doctors noticed that sometimes people with hepatitis B virus
infection (HBV) would get suddenly much worse and go into liver failure, and they didn't know why. But through hard work with what are now antiquated methods, they found out that there was another virus, very different genetically from HBV, but dependent on HBV to spread from person to person. It is called hepatitis D virus
or delta agent, and it steals proteins made by HBV to get from cell to cell and victim to victim. The combination of HBV plus hepatitis D is always much more serious than HBV alone, and hepatitis D virus never occurs on its own. This phenomenon, called viral interference, has been seen in the lab for a while, but it was generally thought to be an artifact with little or no importance in human disease. That’s because we didn’t have the technology to easily find and identify viruses in living people until recently. The advent of PCR
rewrote our understanding of viral interactions, as it did for many areas of biology. We learned that almost everyone has many silent viral infections cooking in them all the time, some that last for life and some that come and go. When the human genome was sequenced, it showed that 8% of the human genome is made up of dormant and disabled retroviruses
(the kind of virus that causes AIDS). It’s as if scientists were looking for cockroaches in a big dark room and all we had was a little flashlight. For decades we followed one bug at a time, and it worked and we made progress, so we thought each one was alone. And then with PCR we found the light switch and yikes, they were everywhere! We didn’t notice most of them for so long because they cause no symptoms in most people. Research since then had shown that viruses can interact with each other in lots of direct and indirect ways. Viruses are parasites; they have to get inside of a cell and use the building blocks of the cell itself to reproduce. If two different viruses try to replicate in the same cell at the same time, they may wind up competing with each other for the building blocks, which can slow their replication down. They also sometimes get their parts mixed up in that situation, and the new viruses released from the cell have some proteins from one virus and some from the other. There are also viruses that cause disease but are unable to move from cell to cell unless another virus infects the cell they are in, like hepatitis D. We call hepatitis B a “helper virus” for hepatitis D, and we now know of many examples like this among animal and plant viruses. The genes of co-infecting viruses can also get combined in strange ways. An extreme example of this is “embedded viruses” where one virus inserts its whole genome into the DNA of another virus---a virus infected by a virus! Viruses can also interact indirectly, by, for instance, changing proteins on the surface of the cell they are in so that other viruses can’t attach and enter. Intriguingly, we have seen some profound beneficial effects from viral interactions. One study showed that curing the common cold might be a very bad idea. A group led by Ian Mackay in Australia collected nasal mucus from 1,247 people with cold-like symptoms and used PCR to test each sample for 17 different kinds of virus known to cause runny noses. People with rhinovirus
infections---the most common type in the group---were eight times less likely to also be infected with flu virus than would been expected if there was no interference
. That’s important because flu kills at least 30,000 people a year in the U.S. while rhinoviruses don’t kill anyone. This protective effect of rhinoviruses has been confirmed by a similar study among military recruits in the U.S. Another beneficial case of interference is that of GB virus
, the virus that causes AIDS. GB virus is passed from person to person in the same ways HIV is, but it doesn’t seem to cause any illness on its own. On the contrary, men who were infected with both GB virus and HIV, before there were drugs to treat AIDS, lived longer and were healthier than men not infected
or whose immune systems destroyed the GB virus. Viral interference has also shown potential to prevent cancers caused by human papillomavirus
, the virus that causes cervical cancer. Human papillomavirus infects only cells near the surface of the cervix and it makes these cells grow faster than they should, sometimes leading to cancer. A parvovirus called AAV
is able to infect those same surface cells, but only if HPV already is in them. Unlike HPV alone, HPV and AAV together cause the cells to die instead of divide
, so tumor formation is averted. AAV is also sexually transmitted, so in this case, two STIs are better than one. Now that we are starting to understand the mechanisms of the interactions,I think that is convincing scientists that viral interference is something to look more closely at now, is, so the attitude has matured from “that’s interesting” to become “this is something we can use to fight disease.” There is a sense that we have conquered the easy targets when it comes to infectious diseases, and the remaining ones are tough, the chronic infections that don’t go away even when your immune system fights them for years. I think understanding viral interference is probably our best hope for eliminating diseases caused by these viruses that establish latent infections, like HIV, hepatitis B and C, some papilloma viruses, and all the herpesviruses. I have already mentioned some examples of natural viruses that produce interference, but engineering interfering viruses could provide many more possibilities. There is a concept in cell biology of dominant negative mutations
. A protein with a dominant negative mutation looks the same as the normal protein but it doesn’t perform the normal protein’s function---like a key that fits in the ignition but doesn’t start the car. We know the functions of many of the essential proteins for HIV and herpesviruses in great detail. It would not be technically difficult to engineer dominant negative versions of these, and make versions of HIV or herpes that express them. In theory, giving such viruses to people who already have wild versions of the viruses would slow or possibly even stop disease, since the mutant viruses would infect the same cell type as the normal virus, but make the inhibitory proteins. Viral interference may also provide a better way to fight influenza epidemics. The anti-flu drugs are only moderately effective. Even if a vaccine is available, it takes at least a week after vaccination for the immune system to react enough to be protective. In contrast, it looks like squirting a dose of cold virus into people’s noses would provide significant protection right away, for several days from a single dose, and the particular strain of flu wouldn’t even need to be known. Of course, they would have a cold, but if it was a bad strain of flu going around it might well be worth it. Looking out much further in the future, we may be able to learn from beneficial virus-virus interactions in plants. Marilyn Roossinck's group found
that a grass that grows near hot springs in Yellowstone National Park is heat tolerant only when it is infected with a fungus and that fungus is infected with a virus. Cure the fungus of the virus, and the heat tolerance goes away! This brings up the topic that there are other ways for a virus infection to be beneficial besides reducing disease. What if a virus infection could improve our resistance to cold or heat, or make us smarter, or happier, or able to synthesize our own essential vitamins? Those are obviously far-off possibilities for now, but they may become realistic in coming decades.
Laura Kasman is a virologist at the Medical University of South Carolina in Charleston.
Image courtesy of brownpau / flickr