Published today in the open-access journal PLoS Pathogens, the study suggests that merely replicating the cytotoxic effects of CD8+ T-cells in developing an HIV vaccine — the dominant model of current research — is not optimal. The authors recommend finding and capitalizing on other virus-suppressing capabilities of those cells, also known as killer T-cells, if a successful vaccine is to be developed.
In the same issue of the journal, investigators from the University of Pennsylvania published a comparable study and arrived at similar results. In addition, a commentary in the journal from a team at the University of New South Wales, Australia, describes the importance of the two studies.
“The cytotoxic activity of CD8+ T-cells by itself is not sufficient to provide ongoing protection from HIV because other virus-suppressive factors produced by these cells are involved,” said Satya Dandekar, senior study author and professor and chair of the Department of Medical Microbiology and Immunology at UC Davis. “The dominant role of these cells in controlling viral infection has yet to be found and may not be entirely linked to their direct-killing abilities. These findings provide us a new direction in identifying the suppressive factors that can be used to prevent or halt HIV infection.”
Lead researcher Joseph Wong, an associate professor of medicine at UCSF, said the outcome should inspire new efforts to identify the factors of CD8+ T-cells that can be leveraged against HIV.
“CD8+ T-cells are vital to an immune system response to viruses, but we clearly don’t know all the factors that make that possible,” said Wong, who was at the VA San Diego Healthcare System and UC San Diego when the study was conducted.
Dandekar, Wong, and their collaborators at UC Berkeley and UC San Diego conducted the research by studying rhesus macaque monkeys at the California National Primate Research Center at UC Davis with simian immunodeficiency virus (SIV) infection. SIV produces in monkeys the same disease that HIV, or human immunodeficiency virus, produces in humans. The researchers used antibodies to eliminate CD8+ T-cells from some of the monkeys and treated the animals with tenofovir and emtricitabine – the same highly active antiretroviral therapy (HAART) medications used to treat HIV in humans.
In animals with reduced CD8+ T-cells, the amount of virus increased dramatically, confirming that the cells have an important role in curtailing viral production. After treating the monkeys with HAART, however, virus levels declined at the same rate and degree, regardless of whether or not the monkeys had CD8+ T-cells. Removal of CD8+ T cells did not alter the lifespan of virus-infected cells. If those cells were actively killing infected cells, the decline would have been much faster in monkeys with intact CD8+ T-cells.
Dandekar and Wong agree that their outcome should encourage refinements of the current HIV vaccine model. Their study emphasizes the need to identify the non-cytotoxic activities of CD8+ T-cells that can be replicated for immuno-therapeutics and vaccine design. New genomics technology can speed that process.
“We hope our finding stimulates a better understanding of what constitutes an effective immune response against HIV,” said Wong.
Other scientists involved in the research were Elizabeth Reay and Sumathi Sankaran-Walters of UC Davis; Satish Pillai of UCSF; Matthew Strain, Caroline Ignacio, David Looney and Theresa Russell of UC San Diego; and Rodin Porrata of UC Berkeley.
The research was supported by the National Institutes of Health.
The UC Davis School of Medicine is among the nation’s leading medical schools, recognized for its specialty- and primary-care programs. The school offers fully accredited master’s degree programs in public health and in informatics, and its combined M.D.-Ph.D. program is training the next generation of physician-scientists to conduct high-impact research and translate discoveries into better clinical care. Along with being a recognized leader in medical research, the school is committed to serving underserved communities and advancing rural health. For further information, visit the UC Davis School of Medicine Web site.
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