Oct. 20, 2000 BOSTON -- A team headed by researchers from Beth Israel Deaconess Medical Center has shown that AIDS vaccines designed to boost the immune response of "killer" T cells were successful in suppressing an unusually virulent strain of the AIDS virus and preventing clinical disease in monkeys, although the vaccine did not prevent infection.
In the study reported in the Oct. 20 issue of Science, all eight animals who received the vaccine remained healthy after being infected with the AIDS virus. The vaccinated animals showed low or undetectable virus levels and no documented clinical disease or death. In comparison, eight animals who received a placebo vaccine showed persistent, high virus levels and significant clinical disease after 140 days, leading to death in half of them.
"We haven't made a vaccine that will prevent AIDS virus infections in humans," says Norman Letvin, M.D., the paper's senior author and chief of viral pathogenesis at Beth Israel Deaconess. "However, the findings in this study suggest that a vaccine might slow disease progression after an infection has occurred and decrease the likelihood of an infected individual transmitting the virus. This could have important ramifications for the AIDS epidemic," says Letvin, also a professor of medicine at Harvard Medical School.
"The findings shed new light on what can be reasonably expected from the candidate AIDS vaccines that are currently under development," say graduate student Xuefel Shen and professor of medicine Robert Siliciano, M.D., Ph.D., both from Johns Hopkins University School of Medicine, in an accompanying perspective article in the same issue of Science. "If the results can be generalized to immunization of humans with HIV-1 vaccines," write Shen and Siliciano, "then we can expect to have vaccines that do not prevent infection with HIV-1 but nevertheless have a significant effect on the course of the disease, potentially improving the quality of life and lifespan of infected individuals."
In 1999, about 5.4 million people were newly infected with HIV and about 2.8 million died of AIDS, according to the most recent estimate by the Joint United Nations Programme on AIDS. Although drug treatments for AIDS have extended lives and kept symptoms at bay for many, the majority of new cases of HIV infection and AIDS are in regions of the world that these costly treatments will never reach. It has become clear that developing an HIV vaccine is a crucial strategy for curbing the pandemic.
The Science paper extends work from Letvin's group published earlier this year in the Proceedings of the National Academy of Science. Led by Dan Barouch, M.D., Ph.D., then a medical student at Harvard Medical School working in Letvin's lab, the researchers showed that the vaccine approach employed in the current study dramatically boosted the immune response to the AIDS virus in monkeys.
Vaccinated infected animals showed five-fold increases in the number of "killer" immune cells, also known as CD8 cytotoxic T lymphocytes, which can attack and contain AIDS-virus-infected cells in both monkeys and people. A steady accumulation of evidence from Letvin's lab and other groups have implicated this arm of the immune system as critical in controlling viral replication.
The Proceedings paper also showed high levels of antibodies in vaccinated animals. However, the virus mutates so quickly that antibody immunity -- which forms the basis of most other vaccines -- is believed to be too restricted in its ability to recognize viruses to be effective in controlling HIV infections.
The cytotoxic T lymphocytes combat AIDS virus infections by killing virally infected cells. In the latest Science study, the vaccinated animals showed stable counts of CD4 T cells (essential immune cells that are usually lost following AIDS virus infections) and low levels of AIDS virus replication. More virus was suppressed in animals with the greatest killer immune cell count, suggesting that the vaccine-induced killer lymphocytes were controlling the viral replication.
In both studies, the researchers used a "naked DNA" plasmid, a circular piece of the AIDS viral gene, which stimulates the immune system to make "killer" immune cells, also known as cytotoxic T lymphocytes. To further boost the immune response, they borrowed a concept from tumor immunology studies and added a fusion protein that included a lymphocyte growth factor. The fusion protein elicited a more sustained immune response when they attached to the DNA vaccine a second plasmid encoding the protein instead of directly injecting the protein. A DNA plasmid is easier to make and transport than a protein, and it can be given once, whereas an injected protein is cleared by the body quickly and must be administered many times to maintain a therapeutic level. In vaccine development, economy and ease of delivery are critical factors, because the ultimate test will be how widely and efficiently the vaccine can be administered in undeveloped or remote areas of the world.
The study was funded by the National Institutes of Health. Other co-authors include Beth Israel Deaconess researchers Sampa Santra, Ph.D., Jorn Schmitz, M.D., Ph.D, Marcelo Kuroda, M.D., Ph.D., Abie Craiu, Ph.D., Xin Xiao Zheng, Georgia Krivulka, Kristin Beaudry, Michelle Lifton, Christine Nickerson, and Terry Strom, M.D.; Ton-Ming Fu, Wendy Trigona, Kara Punt, Dan Freed, Liming Guan, Sheri Dubey, Danilo Casimiro, Adam Simon, Mary-Ellen Davies, Michael Chastain, Emilio Emini, Ph.D., John Shiver, Ph.D., from Merck Research Laboratories; Mark Lewis, Ph.D., from Southern Research Institute; Miroslawa Bilska, Ph.D., and David Montefiori, Ph.D., from Duke University Medical Center; and Rebecca Gelman, Ph.D., from Dana-Farber Cancer Institute.
Beth Israel Deaconess Medical Center is a major patient care, research and teaching affiliate of Harvard Medical School and a founding member of CareGroup Healthcare System. Beth Israel Deaconess is the third largest recipient of National Institutes of Health research funding among independent U.S. teaching hospitals.
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