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R_news.sciencemag.org 2015 03490.txt.txt

#Designer antibodies may rid body of AIDS virus Anti-HIV drugs have extended life for millions of people, but they have eliminated never the virus from anyone. That because HIV integrates its genetic material into the chromosomes of some white blood cells, helping it escape notice of the immune system. Two new studies show that artificial antibodies could edirectthe immune response to these latently infected cells and help drain those HIV reservoirs in the body. But this creative strategy also carries risks. he rationale is sound, and the data are exciting, but we will need to move carefully, says Steven Deeks, an HIV/AIDS clinician at the University of California, San francisco (UCSF), who tests cure strategies. here really is zero room for error. Several previous studies have explored whether drugs can shock cells that are infected with latent HIV to make new viruses, setting them up for the kill by the natural immune response. But this new work ups the ante by designing so-called bispecific antibodies that both promise to reverse latency and then do the mop-up work. he dual activity makes this an attractive new approach, says Sharon Lewin, a HIV cure researcher who directs the Peter Doherty Institute for Infection and Immunity in Melbourne, Australia. t exciting. The two new papers, which only appear online so far, mainly involve test tube experiments. One, described in Nature Communications today, was conducted by a team from the Vaccine Research center at the U s. National Institute of Allergy and Infectious diseases (NIAID) in Bethesda, Maryland. The second study appeared last month in The Journal of Clinical Investigation (JCI) and involved a collaboration between three universities and a biotech company. Both groups designed artificial versions of antibodies, the Y-shaped molecules made by the immune system to target pathogens. With natural antibodies, both rmsof the Y clasp the same target. But the arms of bispecific antibodies each grab a unique protein. In this case both teams designed their antibodies to clasp an HIV protein and CD3, a receptor found on the surface of white blood cells. The bispecific antibodies focus on the CD3 receptor for two reasons. One is that HIV hides its DNA inside white blood cells, or T lymphocytes, that have CD3 receptors. The other is that a second type of CD3-studded lymphocyte known as a killer T cell destroys HIV-infected cells. The bispecific antibody first binds to CD3 on cells that harbor latent HIV. This prompts the cells to divide, an ctivationprocess that wakes up the sleeping virus. New HIV proteins are produced subsequently that migrate to the surface of the cell. Now the bispecific antibody grabs a killer T cell that has a CD3 receptor and, with its second arm, finds a recently activated cell that has HIV proteins on its surface. Bringing the killer T cell in close proximity to the infected cell effectively stuffs the prey into the lion mouth. he molecule works just as you hope it would in several assays, says John Mascola, director of NIAID Vaccine Research center and head of the group reporting the Nature Communications study. But neither team has shown yet that their bispecific antibodies can actually reduce reservoirs of HIV in monkeys which are used commonly to study the AIDS virus. Those studies are underway, and it will take at least a year before either team tests the concepts in HIV-infected people. David Margolis, a virologist at the University of North carolina, Chapel hill, and co-author of the JCI study, says draining a reservoir ultimately may require combining bispecific antibodies with other latency reversing approaches and immune system stimulators like anti-HIV vaccines. UCSF Deeks cautions that anti-CD3 antibodies can cause too much activation of T cells, leading to a massive inflammatory reaction that damages organs and can even cause death. Indeed in one 1999 study of anti-CD3 antibodies used to purge reservoirs in three HIV-infected people, serious side effects, including kidney failure and seizures, promptly surfaced. But the anti-CD3 antibodies in the earlier study had both arms, Mascola notes, which led to far more activation than the single arm in the new bispecific antibodies. He further points out that two cancer bispecific antibodies on the market both have anti-CD3 arms. he key is to find the right balance between CD3 activation and toxicity, Mascola says. hat the real challenge here. c

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