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What's That Virus Doing With My Genes?

Tim Sparer
Department of Microbiology & Immunology
Stanford University School of Medicine
December 2001


As a viral immunologist, I am investigating how viruses have stolen some of our genes for their own purposes. People often think viruses want to hide from our immune system because immune cells normally eliminate invading viruses. However, recently scientists have discovered that instead of avoiding detection from the immune system, the herpesviruses have evolved genes that activate the immune system to aid viral spread to other people. By understanding how viruses manipulate the immune system, I hope to discover ways of disabling these mechanisms to construct a better vaccine.

"In order to defeat your enemies, you must make them your friend and keep them close to you." -- From the TV series "X files".

Herpesviruses coexist and "befriend" the immune system so that they can spread throughout the population. Most readers have a herpesvirus in them. The more common herpesviruses cause cold sores and mononucleosis (mono or kissing disease). These herpesviruses are similar to but not the same as the virus upon which I work. This virus is called cytomegalovirus (CMV, cyto=cell, megalo=big) because when it infects cells, they become enlarged. In the vast majority of cases CMV infection causes no disease at all. Only when CMV infection occurs during pregnancy does CMV lead to mental retardation, hearing loss, and in a few cases even death of the newborn. Understanding how CMV causes disease and spreads will help to develop safe, effective vaccines and treatments.

Recently, scientists have found that CMV carries a gene that resembles a gene from our immune system. This gene produces a protein that attracts cells of the immune system much like the gene in humans. Why would the virus want to attract and trigger the immune system? My research is focusing on this question. My hypothesis is that human CMV triggers the immune system in order to infect the infiltrating cells. These cells will deliver the virus to different organs of the body and eventually to the bone marrow where the virus will remain dormant for the life of the host.

My hypothesis is based on an example from mouse CMV. Mouse CMV produces a protein called MCK. This protein is similar to a normal mouse protein that attracts and activates immune cells. Our lab has shown that the MCK also recruits and activates immune cells and that a mutant mouse CMV lacking MCK cannot disseminate to the salivary glands. Infection of the salivary gland is important for mouse CMV because the virus spreads from one mouse to the next in saliva during biting and licking. These experiments demonstrate that mouse CMV uses MCK to activate the immune system, which allows mouse CMV to spread.

Similarly, there is a protein in human CMV called vCXC-1. Once again, this protein looks like a human protein that attracts and activates human immune cells. I am exploring whether vCXC-1 functions like MCK by aiding viral spread. Like many scientists, I perform experiments on mice, as mice are excellent models for human diseases. In order to use the mouse model for assessing the role of vCXC-1 in viral spread, I had to overcome two obstacles. First, all cytomegaloviruses are species specific (i.e. mouse CMV does not infect humans and human CMV does not infect mice). This means that I cannot infect a mouse with human CMV to see how vCXC-1 functions. Therefore, I generated a mouse CMV with the vCXC-1 gene in it so this modified mouse CMV can infect a mouse and express the vCXC-1 protein. The second barrier was that the vCXC-1 protein does not function on mouse cells. The mouse receptor for vCXC-1 is slightly different so vCXC-1 does not work in mice.
To circumvent this problem, I made a transgenic mouse expressing the human vCXC-1 receptor. Transgenic mice have a gene from another animal inserted into them. In my case, I have inserted the human vCXC-1 receptor gene. I have shown that these transgenic mice respond to vCXC-1 like humans. Now with the modified mouse CMV expressing vCXC-1 and the vCXC-1 receptor transgenic mouse, I'm currently investigating whether vCXC-1 can contribute to the spread of the virus.

If I'm able to show that a virus lacking vCXC-1 cannot spread, eliminating that gene from human CMV could make a good vaccine candidate. This weakened virus-vaccine would still induce a protective immune response without spreading throughout the population.