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Antibody fights AIDS-like disease in monkeys
  Approach being considered for HIV prevention in humans.
Published online 10 December 2008 | Nature | doi:10.1038/news.2008.1295
Heidi Ledford
An antibody treatment has rejuvenated the immune systems of macaques infected with a virus called SIV, allowing the monkeys to fend off the symptoms of an AIDS-like disease for months. SIV is studied as a model for HIV infection in humans, and the therapy could be tested in clinical trials of HIV-infected patients as soon as next year, pending approval by regulators.
The antibody targets a protein called 'programmed death-1' (PD-1), one of several proteins that damp down immune responses during long-term infection by viruses like HIV and hepatitis C. Researchers have recently turned to PD-1 as a possible new therapy for HIV infection, in hopes that shutting down PD-1 signalling would reawaken important immune cells called killer T cells that can attack virus-infected cells (see Light shed on battle against HIV).
Although early results were promising, those experiments were performed in cell cultures and mice - neither of which has a clean record when it comes to predicting how a drug will perform in primates and humans.
"Everybody was still sceptical about it," says Rama Amara, an HIV researcher at the Yerkes National Primate Research Center at Emory University in Atlanta, Georgia. "Even I didn't anticipate it would be this effective in primates."
Amara and his colleagues now report in Nature that blocking PD-1 reduced levels of SIV in the blood of infected macaques1. SIV-infected monkeys who did not receive the treatment succumbed to an AIDS-like disease within five months of the start of the experiment; the nine monkeys who were treated with antibody against PD-1 showed no symptoms over the same time.
In the pipeline
The New Jersey-based antibody company Medarex is already developing PD-1 antibodies for use against cancer and the hepatitis C virus in humans, and early clinical trials are under way. Meanwhile, Amara says that he has communicated with another US company, which he declined to name, that hopes to apply for regulatory approval to begin tests in HIV patients next year.
It is, however, possible that blocking PD-1 could result in overactive T cells that target the body's own cells, causing an unwanted autoimmune response. "It's a big concern in the field how much reactivity you will induce in these cells," says immunologist John Wherry of the Wistar Institute in Philadelphia, Pennsylvania.
So far, however, studies in mice have given no evidence that blocking PD-1 causes autoimmunity, he notes, and the short-term treatment used in Amara's study did not produce adverse side effects.
Amara and his colleagues are now testing the effects on monkeys of longer-term treatment with the antibody. In the published study, macaques were given the antibody four times over ten days; the team is now testing treatment regimes lasting two and three months.
Wherry and his colleagues have also looked at the role of PD-1 in reducing T-cell responses. In a paper published recently in Nature Immunology2, Wherry's lab reported that inhibiting both PD-1 and another protein called LAG-3 boosted T-cell activity more than blocking either protein alone. But so far those experiments have only been carried out in mice. "There are clearly several other pathways that operate in conjunction with PD-1," he says. "Moving forward, we'd like to see examination of these other pathways in SIV and HIV infection as well."
1. Velu, V. et al. Nature advance online publication, doi: 10.1038/nature07662 (2008).
2. Trautmann, L. et al. Nature Immunol. doi: 10.1038/ni.1679 (2008).
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