Vaccines designed to trigger an immune response to a small HIV protein called Tat could be a promising way to fend off the virus, intriguing new data suggest. According to a report in this week's journal "Nature", "killer" T cells targeted to the Tat protein can effectively contain simian immunodeficiency virus (SIV), the monkey version of HIV, during the natural course of early infection.
University of Wisconsin researchers found that these Tat-specific killer T cells eliminated the original strain of SIV four weeks after they exposed 18 rhesus macaque monkeys to the virus. The monkeys still had some SIV, but this SIV differed genetically from the original strain. These small genetic changes, pinpointed by the research team and traced predominantly to the Tat protein, provided enough disguise to enable the virus to escape immune attack.
"These animal studies open the window on immune events in early HIV infection and provide a rationale for exploring a new approach to designing HIV vaccines," says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), which funded the research. "The results suggest that using vaccines that stimulate immune responses against virus proteins produced within a few hours after infection, such as Tat, may help control HIV."
"This is the first time someone has investigated the entire cellular immune response during the acute phase of infection," adds Peggy Johnston, Ph.D., NIAID's assistant director for AIDS vaccines and associate director of the Vaccine and Prevention Research Program in the Institute's Division of AIDS. The cellular immune response primarily consists of killer T cells, which attack infected cells rather than target free virus. "If ongoing work by these investigators shows that vaccinating monkeys with SIV Tat induces a massive killer T-cell response that can prevent infection or substantially reduce the amount of virus in monkeys, research on HIV vaccines that incorporate similar targets will be stimulated."
Current products in human vaccine trials primarily induce immune responses to envelope or other structural proteins of HIV rather than to functional proteins like Tat, which is required for the virus to replicate.
Virus levels peak within weeks after both HIV and SIV infection, but decline soon after when strong killer T-cell responses develop. These responses, however, can hold the virus at bay only so long, eventually losing out to the virus. The power struggle shifts in favor of the virus, the Wisconsin researchers found, because killer T cells pressure the virus to evolve or be destroyed. The challenge remains to design vaccines that induce killer T-cell responses so that the immune system retains the power.
Patricia D'Souza, Ph.D., a microbiologist with NIAID's Division of AIDS and project officer for this study, says cellular immune responses to HIV and SIV have been difficult to investigate, and only recent research developments made this work possible. "Without the availability of genetically typed monkeys, cloned virus and innovative technology in cellular immunity, it would have been impossible for Dr. Watkin's group to detect this massive, early Tat-specific immune response."
The study team, led by professor of pathology and laboratory medicine David Watkins, Ph.D., Todd Allen, Ph.D., and graduate student David O'Connor, conducted the research at the Wisconsin Regional Primate Research Center (RPRC) in Madison. This RPRC is one of eight centers located nationwide that is funded by the National Center for Research Resources, part of the National Institutes of Health (NIH).
NIAID is a component of NIH. NIAID supports basic and applied research to prevent, diagnose and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, tuberculosis, malaria, autoimmune disorders, asthma and allergies.
Press releases, fact sheets and other NIAID-related materials are available via the NIAID home page at http://www.niaid.nih.gov. For additional information on the Regional Primate Research Centers, contact Kathy Kaplan, Information Officer, National Center for Research Resources, 301-435-0888 or visit the NCRR Web site at http://www.ncrr.nih.gov.
1. TM Allen et al. Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viremia. "Nature" 407:386-90(2000).
2. BD Walker and PJR Goulder. Escape from the immune system. "Nature" 407:313-14 (2000).