January 2, 2015
Lisa Newbern, 404-727-7709, email@example.com
Vaccines designed to protect against HIV can backfire and lead to increased rates of infection. This unfortunate effect has been seen in more than one vaccine clinical trial.
Scientists at Yerkes National Primate Research Center, Emory University, have newly published results that support a straightforward explanation for the backfire effect: vaccination may increase the number of immune cells that serve as viral targets. In a nonhuman primate model of HIV transmission, higher levels of viral target cells in gateway mucosal tissues were associated with an increased risk of infection.
The findings, published in Proceedings of the National Academy of Sciences (January 2015), suggest that vaccine researchers, when evaluating potential HIV/AIDS vaccines, may need to steer away from those that activate too many viral target cells in mucosal tissues.
"One of the reasons why it has been so difficult to make an AIDS vaccine is that the virus infects the very cells of the immune system that any vaccine is supposed to induce," says senior author Guido Silvestri, MD, chief of microbiology and immunology at Yerkes National Primate Research Center. Silvestri is also a professor of pathology and laboratory medicine at Emory University School of Medicine and a Georgia Research Alliance Eminent Scholar. The first author of the paper is senior research specialist Diane Carnathan, PhD, and colleagues from the Wistar Institute, Inovio Pharmaceuticals and the University of Pennsylvania contributed to the study.
A large part of the HIV/AIDS vaccine effort has been focused on developing vaccines that stimulate antiviral T cells. T cells come in two main categories, defined by the molecules found on their surfaces. CD8 is a marker for "killer" cells, while CD4 is a marker for "helper" cells. CD4+ T cells are known to be primary targets for HIV and SIV (simian immunodeficiency virus) infection, while several studies have proposed that CD8+ T cells could be valuable in controlling infection.
In this study, researchers immunized rhesus macaques with five different combinations of vaccines encoding SIV proteins found on the inside of the virus only. This experimental strategy was designed to examine the effects of cell-mediated immunity, without stimulating the production of neutralizing antibodies, in what scientists refer to as a "reductionist approach."
The monkeys received an initial immunization followed by two booster shots after 16 and 32 weeks. The monkeys were then exposed to repeated low-dose intrarectal challenge with SIV, once per week, up to 15 times. In general, the immunization regimens did not prevent SIV infection. While all the immunized monkeys had detectable levels of circulating "killer" CD8+ T cells, there was no correlation between these cells and preventing infection.
The most important result, however, was that the monkeys that became infected had higher levels of activated CD4+T cells in rectal biopsies before challenge, Silvestri says. "This study shows that if a vaccine induces high levels of activated CD4+ T cells in mucosal tissues, any potential protective effect of the vaccine may be hampered," he explains.
The study emphasizes the unique challenges that HIV poses in terms of vaccine development, and the importance of pursuing vaccine concepts and products that elicit strong antiviral immune responses without increasing the number of CD4+ T cells in the portals of entry for the virus.
The research was supported by the National Institute of Allergy and Infectious diseases (AI080082) and the NIH Director’s Office of Research Infrastructure Programs (Primate centers: P51OD11132).
Established in 1930, the Yerkes National Primate Research Center paved the way for what has become the National Institutes of Health-funded National Primate Research Center (NPRC) program. For more than eight decades, the Yerkes Research Center has been dedicated to conducting essential basic science and translational research to advance scientific understanding and to improve human health and well-being. Today, the Yerkes Research Center is one of only eight NPRCs. The center provides leadership, training and resources to foster scientific creativity, collaboration and discoveries, and research at the center is grounded in scientific integrity, expert knowledge, respect for colleagues, an open exchange of ideas and compassionate, quality animal care.
In the fields of microbiology and immunology, infectious diseases, pharmacology and drug discovery, transplantation, neurologic and psychiatric diseases, as well as behavioral, cognitive and developmental neuroscience, Yerkes scientists use innovative experimental models and cutting-edge technologies to explore and test transformative concepts aimed at: preventing and treating viral diseases, such as AIDS; designing novel vaccines for infectious diseases, such as malaria and tuberculosis; enhancing the potential of organ transplantation and regenerative medicine; discovering new drugs and drug classes through high-throughput screening; defining the basic neurobiology and genetics of social behavior, and developing new therapies for disorders, such as autism and drug addiction; understanding the biology of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases; and advancing knowledge about the evloutionary links between biology and behavior.
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The Robert W. Woodruff Health Sciences Center of Emory University is an academic health science and service center focused on missions of teaching, research, health care and public service. Its components include the Emory University School of Medicine, Nell Hodgson Woodruff School of Nursing, and Rollins School of Public Health; Yerkes National Primate Research Center; Winship Cancer Institute of Emory University; and Emory Healthcare, the largest, most comprehensive health system in Georgia. Emory Healthcare includes: The Emory Clinic, Emory-Children's Center, Emory University Hospital, Emory University Hospital Midtown, Wesley Woods Center, and Emory University Orthopaedics & Spine Hospital. The Woodruff Health Sciences Center has a $2.5 billion budget, 17,600 employees, 2,500 full-time and 1,500 affiliated faculty, 4,700 students and trainees, and a $5.7 billion economic impact on metro Atlanta.