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MEDICINE Strategy Is Developed to Fortify DNA Vaccine Against the AIDS VirusAlthough 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. But HIV poses unique challenges to vaccine design, and while a number of strategies show promise, none so far has been a breakthrough. Norman Letvin, HMS professor of medicine at Beth Israel Deaconess Medical Center, and Dan Barouch, clinical fellow in medicine at Massachusetts General Hospital, have been working with naked DNA vaccines for HIV. It is a relatively new technology with some attractive features that so far has not provided protection from the virus in animal models. But Letvin and Barouch have found a way to enhance the vaccine with a dose of the body's own immunological weapons. In results published in the April 11 Proceedings of the National Academy of Sciences, they have shown that the immune response to the vaccine can be boosted in nonhuman primates.
Norman Letvin (left) and Dan Barouch have been working to improve DNA vaccines for HIV by boosting them with the body's natural defenses. The Vaccine Defense"With HIV, we are now faced with a unique paradigm for vaccine development," says Letvin. Designing vaccines for polio and smallpox did not require detailed knowledge about how the viruses caused disease. Vaccine development, Letvin says, was not even considered an academic enterprise. There were two approaches to making a preventive vaccine: either use a virus that has been killed but will still elicit an immune response or use a live attenuated virus that has been altered so that it does not cause disease. But with HIV, which targets immune cells, any attenuated virus that replicates enough to cause an immune response may eventually cause disease. "It may simply not be possible to walk on that razor's edge between lack of pathogenicity but enough immunogenicity to cause protection," Letvin says. The virus mutates so quickly that inactivated viruses generate immunity that is too specific to be effective.Researchers are trying to understand which components of the immune response will protect against an HIV infection. Defining protective immunity against HIV is a difficult task because there have been no known cases of complete elimination of the virus after infection. Instead they must look to long-term nonprogressors and people who seem resistant to infection for clues. It has become increasingly evident that antibody-mediated immunity is not sufficient to protect against HIV. Rather, it is crucial also to generate cytotoxic T lymphocytes (CTLs) that can attack and contain HIV-infected cells. These findings suggest that researchers must develop technology that can stimulate a broad range of immunity.
Vaccines augmented with a T cell growth factor significantly improve immune responses in nonhuman primates. In this graph, p11C tetramer binding is an indicator of cytotoxic T cell responses specific to simian immunodeficiency virus (SIV). The plasmid form of IL-2/Ig (right) produces a more sustained response over time than administration of the purified protein (center). Standard errors are shown in gray. Naked DNA vaccines are a recent innovation, brought about by the discovery that a DNA plasmid encoding a viral gene, when injected into muscle cells, will churn out the protein it encodes. This protein production can generate an immune response to the viral protein without the need for a live vaccine vector that many other vaccines use. The approach offers some advantages: it is safe, elicits CTL as well as antibody responses, and can be given multiple times and still generate immunity. "The other potential vaccine technologies either do not generate this broad immune response involving both components of the immune system, or they involve live organisms that could potentially have infectious risks," Barouch says. Dressing Up a Naked VaccineLetvin and Barouch wondered if they could improve the existing DNA vaccine by harnessing one of the components of the immune system to nudge the immune response along. The augmented vaccine would enter both sides of the battle to sway the outcome; it would provide HIV proteins for the immune system to attack while supplying the immunological weapons to make the attack more effective. They chose to use IL-2/Ig, a protein that fuses the cytokine interleukin-2, a T cell growth factor, with a portion of an antibody molecule. By giving IL-2/Ig with the vaccine, they were able to improve antibody responses about 30-fold and CTL responses about fivefold in rhesus monkeys. The CTL improvement is especially encouraging because this arm of the immune system is now seen as critical for control of viral replication, yet many existing HIV vaccine candidates still primarily elicit antibody responses.They also found that rather than directly injecting the IL-2/Ig protein, they could add a second plasmid encoding IL-2/Ig to the DNA vaccine and elicit a more sustained response. "This demonstrates that we don't even have to give those cytokines themselves, but can deliver them as a naked gene and they will have the same effect or even a better effect than giving a protein," Letvin says. A DNA plasmid is easier to make and transport, and it can be given once whereas a 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 research is "an initial step in a logical approach to vaccine development instead of a purely empirical approach," Barouch says. The idea can be applied to other kinds of vaccines or using molecules other than IL-2/Ig. "This opens up a way to try to incrementally improve immune responses," Letvin says. —Courtney Humphries |
