Research legacy expands

What is it that remains behind when a lifetime researcher or professor closes the office door a final time and moves on to other interests?

In the case of Travis McGuire, professor, Department of Veterinary Microbiology and Pathology, who retired last May with 40 years of service to WSU and, ultimately, the world, the final outcome is still expanding and being written.

Though he still carries a part-time appointment, McGuire left behind a legacy of thriving programs and talented individuals who are carrying on his passion, and his vision.

What began as McGuire’s Ph.D. project evolved into work that eventually changed the field of equine immunology and, today, may contribute to the creation of a viable vaccine against the HIV virus that causes AIDS.

This work continues at WSU, as does McGuire’s influence on those he has worked with.

“He taught me the importance of absolute integrity, of maintaining courage when under fire and of doing the right thing no matter what the personal cost,” said former colleague Lance Perryman, dean of the College of Veterinary Medicine and Biomedical Sciences at Colorado State University.

“He was a mentor in all aspects of my life, not just science,” said Terry McElwain, professor and executive director of the Washington Animal Disease Diagnostic Laboratory, who did his postdoctoral degree under McGuire.

HIV connection
The story begins in 1965 when McGuire came to WSU to pursue a Ph.D. in veterinary pathology. He was primarily interested in studying how animals are able to control infectious diseases — which led to the study of immunology. He decided to investigate the equine infectious anemia virus (EIAV), which at the time posed diagnosis and control problems in horses. Though it was considered an “interesting” disease, it had no known human counterpart and was thought only to occur in horses.

Things changed around 1982 when HIV — human immunodeficiency virus — was discovered. It turned out HIV and EIAV are the same type of virus — a lentivirus — but with one big difference. In horses infected with EIAV, most will have recurrent episodes of fever, lethargy and anemia for about the first year of infection and then are able to control the virus through their immune system. Though they never become entirely free of EIAV, they appear healthy and remain quiescent carriers for life.

In people with HIV, the infection often runs a relentless course leading to death. “Investigators working on the human side were very interested to find out just how horses were able to control the lentivirus infection,” said McGuire.

With the resulting influx of new funding, McGuire and his colleagues maneuvered their way through one experiment after another with the hope of finding the key to producing an effective vaccine against EIAV. In general, most vaccines work by creating an antibody response to the exterior protein coat of a virus or bacteria. Unfortunately for vaccine makers, lentivirus has a tendency to alter its genetic sequence — mutating its protein coat — even during an infection. This, along with other complications, makes lentivirus an extremely difficult virus to control.

Killer T cells and vaccine production
Despite the obstacles, the team persevered and eventually focused on the properties of one particular immune cell, the cytotoxic T-lymphocyte or CTL. These are the killer T cells whose job is to recognize and kill other cells in the body that are infected with foreign proteins, such as viruses. If a vaccine could stimulate production of killer T cells, it potentially could protection against EIAV — and also HIV.

The key lay in a type of molecule present on the surface of all cells — the MHC Class 1 molecules. “When the EIA virus infects a cell, the viral proteins get chopped up into small fragments inside the cell. These proteins are then presented on the surface of the cell by the MHC-1 molecules for the killer T cells to recognize and grab,” explained Bob Mealey, assistant professor, Department of Veterinary Microbiology and Pathology, who is now taking over the studies on immune control of EIAV.

“Our EIAV vaccine is designed to stimulate the killer T cell response against these viral proteins,” said Mealey, “and if it works, we should be able to vaccinate and protect a diverse population of horses.”

Preliminary results have been 100 percent. Five out of five Arabian horses have responded to the vaccine by producing killer T cells. Researchers plan to increase the scale of the experiment under an NIH grant.

“This is the first time we have been able to consistently induce the production of killer T cells,” said McGuire. “They are very difficult to induce in horses but they are necessary to get rid of an infection.”

McGuire and Mealey are not alone in their efforts. According to a recent article in Newsweek, Larry Corey, head of the infectious disease program at Fred Hutchinson Cancer Research Center in Seattle, also has been working with NIH to develop HIV vaccines that can elicit killer T cell responses. They report that in both human and animal studies, killer T cells were shown to control HIV replication.

Hall of fame
This October, McGuire was chosen to be inducted into the Equine Research Hall of Fame at the University of Kentucky in Lexington. As one of only 18 equine researchers who have been awarded this honor and the first inductee ever for WSU, McGuire was recognized for the work of his entire career. In particular, his characterization of key components of the horse’s immune system laid the foundation for major changes in the fields of equine immunology and medicine.

In the mid 1970s, before the heightened interest and funding for EIAV research, McGuire and his colleagues investigated infections and the sudden death of newborn foals. He was able to demonstrate that affected foals had very low blood levels of IgG and other immunoglobulins (proteins that play an important role in the immune response).

This was shown to be related to a failure of passive transfer — where foals fail to receive enough protective antibodies from nursing the mare after birth. “This discovery was of great interest to equine clinicians and breeders,” said McGuire. “We were able to immediately develop strategies to increase the survival rate of foals.”

During this study, McGuire and his team discovered another unrecognized disease in Arabian horses called severe combined immunodeficiency (CID). In CID, the horse has no lymphocytes and, therefore, no antibody production, leading to potentially fatal infections.

This discovery led to NIH grants throughout the 1980s and 90s for studying the genetic mechanism of the CID defect. Eventually Perryman, together with other investigators, successfully developed a carrier test to identify the roughly 28 percent of affected mares and stallions — allowing owners to decide whether or not to breed certain horses.

In the end, McGuire modestly admitted, “There are some good things, some promising results, evolving out of all the work we have done over the past 40 years. It’s great to see it being carried on.”