The viruses inside us: can endogenous retroviruses elicit antibodies?

January Moonrise © EEG

Today I would like to discuss a couple of papers that I used as premise for my new thriller Immunity, which will be part of the Apocalypse Weird series, created by Nick Cole, Michael Bunker and Tim Grahl. Just like all my other thrillers, Immunity too, finds its roots in some fascinating facts about genetics, virology and of course immunity.

The premise of the book has to do with something I discussed a long time ago, in one of my very first posts: human endogenous retroviruses, or HERV's, are small portions of our DNA that we acquired from ancient retroviruses that infected germ line cells of our primate ancestors. Basically, these genes came directly from retroviruses that inserted themselves into cells that then became oocytes or spermatozoa and, once fertilized, passed the viral genes to a new individual. These genomic elements are mostly inactivated in adults (meaning they are in a non-coding part of the DNA), but they have been shown to be transcriptionally active during fetal development. The intriguing bit, however, is that expression levels of these genetic elements have been found to be disrupted in subjects with schizophrenia [1].

I'm sure you are all familiar with the disease, which typically manifests itself through hallucinations (mostly auditory ones), delusions, and the inability to distinguish reality from things that only exists in the patient's mind. It's often characterized also by disorganized thoughts and incoherent speech. Nobel laureate John Nash suffered from schizophrenia, and his disease was portrayed in the movie A Beautiful Mind, though in a very fictionalized way. Another famous case is USC professor Elyn Saks, who wrote an award-winning memoir on her life-long battle against schizophrenia.

Retroviruses are sleek little things. They can infect brain cells and integrate their genomes into the host cell's DNA, causing all sorts of damage. For example, some studies have shown that viruses like HIV and HTLV can indeed infect the brain, causing symptoms such as psychosis and depression [2]. The body fights viruses and pathogens by sending its sentinels (natural killer cells, T cells and antibodies) to find them and destroy them. But what happens if the virus is already embedded in our genome, as is the case with HERVs? Those viral elements have been part of our genome for millions of years, so, in theory, our immune system is not supposed to 'see' them.

 One of the most marvelous and yet most delicate mechanisms that is at the foundation of our immune system is its ability to distinguish self from non-self. T cells and B cells have to undergo strict scrutiny to make sure that they don't mistakenly attack cells of our own body thinking that they are pathogens. This mechanism is tough but not perfect, and failures to recognize self from non-self are at the basis of numerous auto-immune disorders. Autoimmune thyroditis, for example, is an inflammation of the thyroid caused by antibodies attacking the thyroid.

One natural hypothesis as to why HERVs expression levels could be disrupted in a disease like schizophrenia could be that the body is producing antibodies against those genetic elements. This hypothesis cannot be tested directly because, as Dickerson et al. explain in [1], there are no available reagents. However, one can look for antibodies that recognize retroviruses like murine leukemia virus (MuLV), Mason-Pfizer monkey virus (MPMV), and feline immunodeficiency virus (FIV) because they have enough similarities with HERVs.

Dickerson et al. measured the levels of antibodies against these viruses in a population of 666 study subjects, of which 163 with a recent onset of psychosis, 268 with multi-episode schizophrenia, not of recent onset, and 235 controls without a history of psychiatric disorders. They found a significant increase in antibody levels in the recent onset group compared to controls, but not in the multi-episode group compared to controls. At the same time, these subjects had no traces of the actual viruses in their bodies, indicating that the antibody response had to be elicited by the endogenous elements (instead of an active infection). Another study [2] looked for an enzyme called reverse transcriptase, which is a marker for retroviral activity, and found that it was 4 times higher in the cerebrospinal fluid of patients with recent onset of schizophrenia compared to controls.

Many autoimmune disorders are caused by the immune system suddenly attacking its own self. I've used this premise before in my books: Track Presius, the main character in Chimeras, has elevated levels of anti-nuclear antibodies, which are antibodies that, in high concentrations, can cause different immunological disorders as they tend to bind to human antigens.

What intrigued me about the HERV-schizophrenia association, though, was: the researchers tested the presence of antibodies against HERV's using viruses that are not commonly found. What if, instead, a common virus like the flu did bear resemblance to the HERV elements in our brain? In order to fight the infection, our body would have to start producing antibodies that could potentially attack those human genes, too. What would then happen to the brain, suddenly under attack by its own antibodies?

I don't know the real answer, but I can tell you that I had fun speculating about it in my novel. Immunity will be released in April and it will be part of the Apocalypse Weird series.

[1] Dickerson F, Lillehoj E, Stallings C, Wiley M, Origoni A, Vaughan C, Khushalani S, Sabunciyan S, & Yolken R (2012). Antibodies to retroviruses in recent onset psychosis and multi-episode schizophrenia. Schizophrenia research, 138 (2-3), 198-205 PMID: 22542615

[2] Yolken R (2004). Viruses and schizophrenia: a focus on herpes simplex virus. Herpes : the journal of the IHMF, 11 Suppl 2 PMID: 15319094