Led by researchers at Beth Israel Deaconess Medical Center (BIDMC) and the Vaccine Research Center (VRC) at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, the findings appear in the June 9 issue of the journal Science.
"Over the last decade, we have created AIDS vaccines that generate T-cell populations that can combat HIV," explains lead author Norman Letvin, M.D., chief of the Division of Viral Pathogenesis at BIDMC, professor of Medicine at Harvard Medical School, and investigator at the NIAID VRC. "These latest findings now provide us with an important new way of looking at subpopulations of CD4 helper T-cells and suggest how they may be used as a marker to gauge the efficacy of these vaccines."
The work was spearheaded by Letvin and his colleagues at the VRC, which is dedicated to improving global human health through the rigorous pursuit of effective vaccines for human diseases such as AIDS. Since it was first identified 25 years ago, the human immunodeficiency virus (HIV) has proven extraordinarily difficult to control. Attempts to develop an HIV vaccine that triggers the production of antibodies -- the mechanism responsible for vaccine protection against other viruses including polio and hepatitis B -- have been unsuccessful.
"HIV mutates so quickly it can evade antibody immunity," explains Letvin. Instead, Letvin and other scientists in this field have focused their work on developing a vaccine that confers cellular immunity, so that a group of T-cells induced by a vaccine recognizes the cells that have been infected by HIV and then destroys them so that the virus cannot continue replicating.
"While this vaccine approach cannot actually prevent an infection, it can tamp down the AIDS virus, resulting in the development of a much milder form of the disease in vaccinated monkeys that subsequently become infected," he adds. "We know this because the loss of helper T-cells is much less dramatic, the amount of virus replication is much less and the infected animals go on to live longer."
Until now, the success or failure of this type of T-cell vaccine has been determined by measures of virus levels and total counts of CD4+ helper T-cells, which are indicative of infection control in monkeys infected with the AIDS virus.
As in previous studies, this new research found that among monkeys infected with the simian immunodeficiency virus (SIV) -- 24 of which were vaccinated and six of which were not -- the immunity generated by the vaccine controlled infection for approximately 100 days before levels of virus increased and T-cell counts dropped.
But instead of ending the experiment at this point -- assuming that the vaccine conferred protection for only 100 days -- Letvin and his VRC colleagues decided to follow the monkeys for an additional 750 days, a total of 850 days or nearly three years.
"We found that the vaccinated monkeys lived significantly longer than the unvaccinated monkeys following infection and that levels of memory CD4+ cells remained significantly higher in the vaccinated animals," explains Letvin. "This suggests that the initial protection that the vaccine provides in the early weeks following infection gives the monkeys a long-term survival advantage, and that this protection is associated with a significantly higher level of memory CD4+ cells."
In another aspect of the study, Letvin and his colleagues at the VRC found that measurements of a subset of memory CD4+ T cells -- central memory CD4+ T cells -- could help predict how the vaccinated monkeys would fare over the long run.
"This second finding provides us with an important marker to use in gauging the vaccine's performance," says Letvin. "By measuring the levels of central memory cells in blood samples taken from participants in human clinical trials [to test the AIDS vaccine] scientists would be able to predict how well the vaccine would work over time."
More than 30 million individuals -- a majority in the world's developing nations -- have died of AIDS since it was first identified 25 years ago.
"This research underscores the importance of the preservation of memory CD4+ T cells for the long-term health of the HIV-infected individual," says Letvin. "It also suggests that the measurement of this cell in the blood of vaccinated individuals who subsequently become infected with HIV may provide an important predictor of vaccine efficacy."
Study coauthors include BIDMC investigators Yue Sun, M.D., Darci Gorgone, M.A., Adam Buzby, A.B., Jorn Schmitz, M.D., and Brianne Barker, A.B.; John Mascola, M.D., Ling Xu, M.D., Zhi-yong Yang, M.D., Bimal Chakrabarti, M.D., Srinivas Rao, D.V.M., Ph.D., and Gary Nabel, M.D., Ph.D., of the NIAID VRC; David Montefiori, Ph.D., of Duke University Medical Center; and Fred Bookstein, Ph.D., of the University of Washington, Seattle and the University of Vienna, Austria.
This study was supported by the NIAID.
Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and ranks fourth among independent hospitals nationwide in National Institutes of Health funding. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.harvard.edu.
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