2002 defensins paper retracted

The four-paragraph letter in Science last week (January 23) partially retracting the 2002 Science paper by David D. Ho and colleagues identifying the elusive CD8+ cell antiviral factor (CAF) generated headlines, but other researchers in the field said it confirmed what they had suspected for some time. The letter reported that the compounds, called α-defensins 1, 2, and 3, were actually from neutrophils in the cell culture being used, rather than being CAF.Ralf Geiben-Lynn, founder of Acceleration Biopharmaceuticals in Boston, a startup company trying to commercialize an anti-HIV activity he discovered in CD8+ cultures, said that HIV researchers were not surprised by the partial retraction. They had been skeptical from the first announcement of that work, he told The Scientist.Jay A. Levy, of the University of California, San Francisco, after reading a preprint of the 2002 paper, had told Ho to “Be careful,” Levy told The Scientist. Although defensins are made by a variety of cell types including neutrophils and natural killer cells, his group had never seen them come from CD8+ cells, and he predicted that cells in the coculture likely made them. “Well, that's exactly what happened,” he said.Researchers have for years been trying to uncover why some HIV-infected people never progress to AIDS. In 1986, Levy's lab described an activity in these patients' CD8+ T cells that halted the replication of the virus without killing the infected cells, and researchers have been trying to identify CAF ever since.Then, in 2002, Ho's group at the Aaron Diamond AIDS Research Center announced that they had identified α-defensin 1, 2, and 3 in cultures of long-term HIV-1 nonprogressors' CD8+ T cells. The low molecular weight defensins had strong anti-HIV activity, were located by flow cytometry in the CD8+ cells, and were not cytotoxic. They also found that neutralizing them neutralized most of the culture's anti-HIV activity not attributable to the β-chemokines. In short, the authors saw “α-defensin 1, 2, and 3 as a major component of the long-sought-after CAF.”But labs including Levy's and Mary E. Klotman's at the Mount Sinai School of Medicine were unable to reproduce the results, although they were able to corroborate the anti-HIV effect of the defensins. “What the Ho retraction did was explain the contradiction that we had been aware of for some time,” University of California, Los Angeles, defensin researcher Tomas Ganz told The Scientist.The 2002 paper forced many in the field to reassess their own research, Klotman said. Scientists didn't “want to rediscover the wheel,” she said. Levy said that it was difficult to find funding when grant reviewers believed that CAF had already been found. And Geiben-Lynn said that he thinks that the National Institutes of Health and venture capitalists have been turned off by the 16- to 17-year odyssey to identify CAF. He said it is unclear whether Ho's retraction will convince funders that the factor is still out there or whether it is just another indication of the field's lack of progress.Klotman said that some scientists believe there are many natural inhibitors of viruses, the most potent of which have already been discovered, but that others in the field—including herself and Levy—think that there is one significant inhibitor out there that has yet to be been identified.Linqi Zhang, the 2002 Science paper's first author, said that despite the partial retraction, the study was still a significant finding. “Based on a PubMed search,” he told The Scientist, “we are the first group to identify human α-defensin inhibiting HIV.”University of Central Florida neutrophil researcher Alexander M. Cole agreed. “It brings to light a number of questions regarding the potential interactions of neutrophils, neutrophil products, and lymphocyte populations,” he wrote in an E-mail to The Scientist. “It will therefore still be necessary to define the true biological role of α-defensins in the context of preventing HIV.”

2002 defensins paper retracted

Researchers unsurprised that source of compounds was culture neutrophils, not CD8+ cells

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