BioWorld International Correspondent
LONDON - A team of Chinese and French researchers has successfully treated rhesus macaques infected with the simian immunodeficiency virus with a novel type of immunotherapy. The scientists, working in Paris, plan to begin a clinical trial to treat patients infected with HIV using the same approach in early 2003.
Louis Wei Lu, chief investigator at the Saints-Peres Biomedical Center in Paris, told BioWorld International, "We are tremendously excited about the macaque study. This discovery is very important for those with HIV and AIDS. It is also extremely important for all those suffering from chronic viral infections, such as hepatitis B, and infections with intracellular pathogens, such as Mycobacterium tuberculosis, because we believe that it will be possible to generalize this technique to treat these types of infections."
The team is currently trying to find the best protocol for the immunotherapy of SIV-infected macaques, with the aim of trying to eradicate the virus from the body. "We hope we will be able to do that," Wei Lu said. "If we can, this could be a real cure for chronic infections of this type."
An account of the macaque study appears in the Dec. 23, 2002, advance online publication of Nature Medicine in a paper titled "Therapeutic dendritic-cell vaccine for simian AIDS."
Commenting on the paper in a News & Views article in the same issue of Nature Medicine, Bruce Walker of Harvard Medical School said the data are "surprising and unexpected. If the approach is confirmed in monkeys and successfully adapted in humans, it may represent a major new therapeutic approach to HIV-1."
The approach of Wei Lu and his colleagues capitalizes on the observation that the antigen-presenting cells known as dendritic cells are essential if the body is to initiate and maintain virus-specific cellular and humoral immunity. Researchers had postulated that the immune deficiency characteristic of humans and simians infected with HIV and SIV, respectively, was due to the absence and/or abnormal function of dendritic cells, which were unable to stimulate the production of functional virus-specific cytotoxic killer T cells and neutralizing antibodies.
Wei Lu's group had the idea of stimulating dendritic cells (differentiated in vitro from peripheral blood monocytes) with inactivated virus. Virus can be inactivated with AT-2, a chemical that wipes out the virus' ability to replicate, without altering the conformation of its proteins in any way. The group had already shown that, in vitro, dendritic cells that had been exposed to HIV which had been inactivated with AT-2 could stimulate potent antiviral cytotoxic T lymphocytes.
For their latest study, the group isolated dendritic cells from 10 SIV-infected monkeys. In the laboratory, they added to these cells that had been inactivated with AT-2. Next, they infused back into each animal its own treated cells. The animals received five subcutaneous injections at two-week intervals.
Wei Lu said, "Just five weeks after the first immunization, we saw in the 10 vaccinated animals a 1000-fold drop in plasma SIV RNA, and a 50-fold drop of blood cellular SIV DNA, coupled with a peak increase of circulating anti-SIV cytotoxic T lymphocytes. The blood CD4 count increased significantly from week 13, and neutralizing antibodies appeared in the bloodstream." By contrast, in four infected but unvaccinated animals, viral load and CD4 counts remained unchanged, and there were no neutralizing antibodies during 300 days of follow-up.
Biopsies of lymph nodes of the vaccinated animals showed that SIV-specific cytotoxic T lymphocytes were killing SIV-infected cells. The lymph nodes of vaccinated animals also failed to show destruction of the follicular dendritic cell network of the lymph nodes, which is normally a hallmark of HIV/AIDS. During 300 days of follow-up after the first vaccination, immunity to SIV remained strong and stable in seven animals, but declined progressively in the remaining three.
Wei Lu said that he hoped to know within a year whether a similar approach could work in humans. He said he believed therapy of this kind could be rolled out to people in developing countries as well as those with advanced health care systems. "It is easy to generate dendritic cells from peripheral blood monocytes and to load them with inactivated virus from the same person," he said. "The fact that the person is reinjected with both his or her own cells, and the same virus he or she is infected with, is reassuring. Furthermore, unlike antiviral therapy, this strategy is unlikely to have major side effects."
A further advantage is that if the virus mutates to evade the immune response, it would be an easy task to reprime the immune system with the mutant isolates, simply by isolating them.