Overwhelmed. The arrows show how five unusually powerful antibodies attach to different parts of the HIV surface protein.
William Schief / The Scripps Research Institute and the International AIDS Vaccine Initiative
The fight against HIV with antibodies is like fighting against a forest fire with hoses watering. They can slow down the virus, but copies itself vigorously, making mutant versions that dodge this critical immune response. Now, experience suggests that infusing the mice with rare antibodies, exceptionally powerful products in laboratories and then combined into a cocktail might work as a treatment to supplement or even replace antiretrovirals (ARVs). It is a long way from mouse to man, and the cost of production of therapeutic antibodies can be prohibitive. But the concept intrigues many researchers.
The most potent antibodies against HIV are isolated from untreated individuals who failed to control their HIV infection for many years. These so-called neutralizing antibodies (bNAbs) do little to help the people who produce them, but their existence shows that mutations have created a population increasingly diverse virus, prompting the immune system to evolve a response which is both more potent and works against more variants. Unfortunately, the virus mutates easily around bNAbs of each individual, too. But a team led by immunologist Michel Nussenzweig of Rockefeller University in New York showed that it may be possible to thwart the virus by combining several bNAbs that target different parts of it.
As Nussenzweig and colleagues explain in a paper published online today in Nature , they tested bNAbs in a "humanized" mouse model. HIV can not copy itself to mouse cells, so they bought mice that had deliberately crippled immune system, then rebuilt with human stem cells. After infecting mice with HIV, the group tested five different bNAbs recently isolated from humans and artificially produced in laboratory monoclonal cultures.
ARV cocktails are extremely effective in treating people infected with HIV, but the drugs have serious long-term toxicities and should be taken daily. In addition, several clinical studies have shown that even when ARVs completely suppress HIV for years, viral levels rise almost always sharply in the weeks following discontinuation of therapy. If bNAb therapy worked, it would have distinct advantages, says Nussenzweig. "These antibodies are a natural product of man and should not have many side effects, and they can be very long," he said. "Potentially, they could be used twice or three times a year."
When the researchers tested the bNAbs as monotherapies, the levels of HIV generally decreased but rebounded in 2 weeks after stopping treatment, the virus mutated to escape the given antibody. A cocktail three bNAbs that GLOM the surface protein of HIV at different Fared places only slightly better. But when combined investigators five different bNAbs (see graph), the virus remained suppressed in seven of eight mice for 60 days.
therethe idea lost steam bNAb therapy many years after two small-scale human studies have failed. in the June 05 issue of Nature Medicine , a group led by Alexandra of Trkola the University of Zurich in Switzerland described how he had little success with a cocktail of three bNAbs given in 14 humans infected with HIV. Trkola but noted that the existing bNAbs had so much less punch than those available today. "The powerful new monoclonal antibodies and new humanized mouse models undoubtedly open up fantastic opportunities," she said.
immunologist Dennis Burton, who specializes in bNAbs against HIV at the Scripps Research Institute in San Diego, California, said the concept "exciting" "still has a long way to go" before therapy bNAb proves its value by the HIV. firstly infected humans, HIV does not copy itself to particularly high levels in the humanized mouse, meaning that those infected for many years have much more diverse swarms virus which would be more difficult for bNAbs to thwart These mice also do not have an intact immune system.. humans can develop antibodies against monoclonal antibodies, rendering them ineffective in strictly practical terms, the monoclonal antibodies are expensive and difficult to produce in large quantities.
Nussenzweig realizes the challenges. "this does not mean it will work in people," he said. "I think what it means is that it has to be tested in people."
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