HIV vaccine science has hit a bit of a wall. For a vaccine to be really effective, it should be able to recruit different areas of the immune system. It should get one set of immune cells, called helper T cells, to recognize the AIDS virus and spur on another set of immune cells, the killer T cells, to identify the invader so they can hunt down and destroy it. But current vaccines in the pipeline require multiple doses to elicit only limited action from these cells, and are not inducing helper and killer cells to proliferate to the high levels that may be required.
Now, Rockefeller University researchers on the hunt for a new approach have evidence that targeting a third group of immune cells, dendritic cells, may be even more effective than they'd previously believed. A team led by Ralph M. Steinman, the Henry G. Kunkel Professor and head of the Laboratory of Cellular Physiology and Immunology, takes the first step toward determining whether an experimental dendritic cell vaccine might work in humans. They reported their findings the week of Jan. 22 in the advance online edition of the Proceedings of the National Academy of Sciences.
Dendritic cells orchestrate the body's immune response, and prior work by Steinman in mice had shown that targeting an HIV protein to a specific dendritic cell receptor, DEC-205, induced strong helper T cell and killer T cell responses. In the current paper, Steinman and his colleagues -- including Michel Nussenzweig, Sherman Fairchild Professor at Rockefeller and an investigator at the Howard Hughes Medical Institute, and Martin Markowitz, an Aaron Diamond professor at Rockefeller and clinical director at the
The key lies in scaffolding molecules on the cell surface called major histocompatibility complex (MHC) proteins. MHC proteins display foreign particles, or antigens, to immune cells in order to teach them what to look for. MHC molecules have two dominant forms: MHC class I proteins, which present antigens to killer T cells, and MHC class II proteins, which present to helper T cells. One of the reasons researchers have had a difficult time developing an HIV vaccine is because MHC class I molecules typically present antigens only during an infection, when killer T cells are needed to quash an invader.
Steinman and his colleagues got around this problem by taking advantage of an ability that seems best developed in dendritic cells, a pathway known as cross presentation that allows them to process antigens for MHC class I proteins even in the absence of an infection. By targeting a protein from gag, HIV's major structural gene, directly to dendritic cells in blood from 11 people already infected with HIV, Steinman and his colleagues found that dendritic cells processed the protein and cross-presented it for presentation on MHC class I molecules, stimulating a killer T cell response. "We were trying to establish that we could achieve this cross presentation with our vaccine," Steinman says.
Evidence of just how effective the approach could be came when the researchers looked at the extent of their subjects' response. Because different people have slightly different forms of MHC molecules, determined by different versions of the MHC genes, they weren't sure how many people would respond to the single gag protein they'd used. "We just didn't think that it was going to be possible, with this one little protein, to see presentation in almost every individual we studied," Steinman says. "We thought that only a few genetic forms of these class I molecules would work." And because prior research on cross presentation had shown that any given protein would be presented on only one or two forms of the MHC molecule, the researchers were surprised to see that almost all of their subjects showed MHC class I presentation, and with eight different gag protein peptides.
"We probably have a very efficient mechanism of delivering antigens to that class I pathway, using the DEC-205 receptor," Steinman says. The research also implies that the gag protein they selected is quite efficient, making it a good vaccine option. "There are several well conserved regions in gag," he says, "so a single gag protein vaccine may be able to immunize many people to many different forms of HIV." That's further down the line -- their next step is to develop their vaccine so that it can be tested in humans.
Source: Rockefeller University