Duke Medical Center researchers have shown that the protein produced by an artificial HIV-1 gene triggers anti-HIV-1 immune responses in animals. Such proteins could serve as a basis for vaccines that protect against many strains.
Showing that artificial genes produce biologically functional proteins is a significant step in HIV vaccine development, the researchers say. "This study is proof we can induce both cellular and humoral immune responses using an artificial HIV-1 gene. This is a beachhead from which we can move forward in vaccine development," says Feng Gao, a physician, associate research professor of medicine at the medical center, and lead author of the study. Cellular immune responses are those made by specialized immune cells, called "killer T" cells and "helper T" cells, while humoral immune responses are those made by proteins called antibodies, circulating in the blood.
The researchers published their findings in the January 2005 issue of the Journal of Virology. In their experiments, Gao and his colleagues found that the protein produced by the artificially synthesized HIV-1 envelope gene, called CON6, works in much the same way as corresponding natural HIV-1 proteins. The protein binds to surface molecules on the human immune-system cells that are the primary portal by which HIV-1 enters and infects the cells. They also found that antibodies in blood from humans infected with different HIV-1 subtypes recognized and reacted with the protein from the CON6 gene better than natural HIV envelope proteins.
In guinea pigs, the artificially produced protein successfully induced neutralizing antibodies against some HIV-1 strains, although the level was weak. And in mice, vaccines made with the artificial gene induced an anti-HIV-1 response in T cells, the immune system's principal infection fighters.
The synthetic CON6 gene was designed via computer at Los Alamos National Laboratory to be "centralized"--as similar as possible to many genetic subtypes of the most common strains of HIV-1 in the world. The strains, known as M group, contain nine subtypes and are responsible for over 90 percent of global infections. The researchers hope the new gene will help circumvent HIV-1's high levels of genetic variation, which may give the virus an ability to evade attack by an immune system primed to different genetic variants.
"The variations among HIV-1 subtypes make vaccine development very difficult," Gao says. "Centralized genes, designed on computers, could be useful in developing vaccines for areas where several HIV-1 subtypes are circulating. However, because centralized genes are artificially made, there has been great concern that these genes might not be able to perform the biological functions of native genes."
The human body produces an immune response against HIV-1 about two to four weeks after exposure to the virus. Killer T and B immune-system cells reduce HIV-1 levels by attacking the invading virus and infected cells. Despite this massive effort, some HIV-1 can escape the body's defenses, especially if the virus mutates within its human host and is no longer vulnerable to the original immune responses. A vaccine that stimulates both cross-reactive neutralizing antibody and T cell responses against HIV-1 could be the best way to protect against infection, says Gao.