Viral Tethers:
A Concept to Explain the Long and Often Hidden Life of Latent Viruses

Murray Cotter and Erle Robertson

U-M cancer researchers Erle Robertson, Ph.D., associate professor of microbiology and immunology, and graduate student Murray Cotter have authored the first study to identify a specific tethering mechanism between a virus and its host cell. Their findings were published in the November 25, 1999, issue of Virology.

Robertson and Cotter have discovered how some viruses can hide inside the nucleus of human cells for long periods of time—without producing symptoms or triggering an immune response—by attaching to host cell chromosomes. The viruses survive by going dormant until a weakened immune system allows infected cells to again begin multiplying wildly.

Robertson and Cotter describe a series of experiments with Kaposi’s sarcoma-associated herpes-virus or KSHV—a human virus associated with the type of cancer called Kaposi’s sarcoma. In their studies, Robertson and Cotter found a protein expressed by one gene on the virus that builds a biochemical docking station that links viral DNA to the chromosomes of lymphoma cells.

KSHV is one of a family of gammaherpesviruses known to remain dormant in humans long after the initial infection is over. Other similar viruses include the Epstein-Barr virus; the human papilloma virus, which causes cervical cancer; and viruses responsible for hepatitis B and hepatitis C.

“We’ve always suspected that latent viral DNA couldn’t survive long-term within cells without some type of tethering,” says Robertson. “But the latency mechanism for these viruses has been a black box. Now we have a key that will get us in the front door.”

Using cultures of lymphoma cells infected with KSHV, Robertson and Cotter identified a protein called the latency-associated nuclear antigen or LANA, which is expressed by one of approximately 80 genes encoded by the virus. They found that LANA binds to three regions of the KSHV genome, but is most likely to lock onto one specific region for tethering the virus to host chromosomes.
In addition to viral DNA, the U-M scientists found that LANA also binds to histones—small proteins that link bundles of DNA called nucleosomes to make chromatin fibers, which are folded and packed to form chromosomes.

“The results suggest a biochemical mechanism that binds elements of viral DNA to host chromosomes through the interaction of LANA, histone H1, and possibly other chromosomal proteins,” Robertson says.

Robertson has evidence of a similar tethering mechanism in the Epstein-Barr virus, which infects immune system cells called B-lymphocytes. Associated with several varieties of cancer, including breast cancer, Epstein-Barr virus is found in more than 90 percent of the world’s population. In most people, a healthy immune system keeps the virus suppressed. If something upsets the balance between virus and immune response, however, the virus can re-activate. The trigger that signals a dormant virus to begin multiplying and infecting new cells remains unknown, according to Robertson.