Researchers at the Vaccine and Gene Therapy Institute (VGTI) and the Oregon National Primate Research Center at Oregon Health & Science University have received a $3.5 million grant from the National Institutes of Health to develop new methods for vaccinating humans against human immunodeficiency virus (HIV), the virus that causes AIDS. Louis Picker, M.D., associate director of the VGTI and director of the institute's vaccine program, will serve as principal investigator of the five-year study. The National Institute of Allergy and Infectious Diseases, a component of the National Institutes of Health, is funding this research.
The research team is hoping to develop a new class of viral vaccine vectors to serve as the basis of HIV vaccine. Vectors are modified viruses used to safely deliver proteins from a disease-causing virus to the body. Vectors infect individuals, but do not cause any disease themselves. Rather, they serve to present the proteins from a disease-causing virus to the vaccinated person's immune system. This presentation allows the system to generate an immune response capable of protecting the vaccinated person from subsequent encounters with the disease-causing virus.
Most of the HIV vaccine development to date has focused on weakened viral vectors designed to infect the vaccinated person only briefly, insuring that the vector itself does not persist and potentially cause problems. For example, current approaches for HIV vaccines include weakened versions of the smallpox vaccine virus (vaccinia) or adenovirus engineered to produce HIV proteins. Both of these vectors can only survive for a limited time in the human body before they are eliminated by the immune system. While these vectors can generate high anti-HIV immune responses immediately following vaccination, these responses decline with time and may not produce an immune response of the correct characteristics to contain a chronic aggressive virus like HIV.
"Unlike other infectious diseases successfully countered by vaccines, HIV is very robust and able to evade most immune responses," explained Picker. "One theory about why the AIDS vaccines developed so far have not been entirely effective is because they provide only a brief period of time for the anti-HIV immune response to develop, perhaps compromising the protective capacity of the response as well as its ability to persist over subsequent years. We believe a persistent viral vector could produce a superior and more durable anti-HIV immune response that would, in effect, hold the line against HIV."
The OHSU researchers are hoping to develop a viral vector based on cytomegalovirus (CMV). It's believed that approximately 70 percent to 90 percent of the population currently is infected with CMV, a virus that causes little to no effects in immunologically normal hosts, but generates large immune responses that persist for life. CMV vectors have the capacity to re-infect such already infected individuals and generate immune responses to new proteins engineered into the vector. To develop and test this vaccine method, scientists will study animals at OHSU's Oregon National Primate Research Center.
"What makes CMV such an attractive viral vector is a combination of its strong ability to stimulate immune responses and its limited effect on the host," explained Jay Nelson, Ph.D., director of the VGTI and a co-investigator of the study. "More importantly, CMV infections last a lifetime. Therefore, we believe that HIV proteins delivered through a modified CMV vector may boost and maintain anti-HIV immunity enough to protect a person against AIDS throughout his or her lifetime."
In addition to constructing and testing candidate vector based on CMV, the scientists will measure its effectiveness. Investigators will also test vaccine delivery methods and further explore the reasons behind previous AIDS vaccine failures.
Additional research collaborators for this project include Duke University and the Wisconsin National Primate Research Center.
Louis Picker, M.D., associate director of the OHSU Vaccine and Gene Therapy Institute and director of the institute's vaccine program; professor of pathology in the OHSU School of Medicine; and director of the Pathobiology and Immunology Division of the Oregon National Primate Research Center.
Jay Nelson, Ph.D., director of the OHSU Vaccine and Gene Therapy Institute; professor of molecular microbiology and immunology in the OHSU School of Medicine; and scientist in the Pathobiology and Immunology Division of the Oregon National Primate Research Center.