Scientists Claim to Have Found Family of Proteins That Blocks HIV Replication; Leading HIV Researchers Skeptical
A group of researchers led by Dr. David Ho of the Aaron Diamond AIDS Research Center in New York yesterday announced that they have identified a family of three proteins present in HIV-positive long-term non-progressors that block HIV replication and could reveal a new way to combat the disease. However, several leading HIV/AIDS researchers remained skeptical, the Los Angeles Times reports (Maugh, Los Angeles Times, 9/27). The proteins, called alpha-defensins -- which are found in white blood cells called neutrophils that attack bacteria and parasites and not viruses like HIV -- were first discovered in 1985 and function as natural "antibiotics." In yesterday's online edition of the journal Science, Ho's team reported that they found alpha-defensins in CD8+ T cells, a type of immune cell in which alpha-defensins had previously not been identified (Brown, Washington Post, 9/27). Dr. Jay Levy of the University of California-San Francisco was the first researcher to reveal that CD8 cells exhibited a protective antiviral factor, which he called CAF, in some people with HIV. Between 1% and 5% of people with HIV can live untreated with the disease for 10 to 15 years or more without developing AIDS-like symptoms due to an unknown immune response in their body, which researchers have been attempting to identify for years. In a quest to find CAF, which Levy has not been able to identify, Ho and colleagues drew CD8 cells from three long-term non-progressors (Pollack, New York Times, 9/27). The cells were cultured, and then HIV and CD4+ T cells, HIV's main target, were added to the cultures. HIV was unable to infect the CD4 cells in the presence of the cultured CD8 cells. The researchers then added antibodies against the three defensins to cultures, essentially inactivating them. When HIV and CD4 cells were added, the cells were "easily" infected, the researchers reported (Washington Post, 9/27). The researchers performed other tests, including washing the CD8 cells over a new kind of protein chip developed by Ciphergen Biosystems of Fremont, Calif., to prove that the defensins were present. The chips were then read by a mass spectrometer to determine their weight, and the alpha-defensins were identified (New York Times, 9/27).
Skepticism and Questions Over Methods
Although Ho, whose previous discoveries "helped pave the way" for combination antiretroviral therapy, hailed the discovery, several leading HIV/AIDS researchers yesterday said they were not convinced by the team's research. "This is not it. I'll be frank," Levy said, adding, "We know [CAF is] secreted by CD8 cells, and we know it blocks transcription of the virus -- that is, it blocks the virus after it enters the cell." In contrast, the defensins used by Ho appeared to block HIV from entering cells. Levy said he is still unsure whether the defensins came from the CD8 cells or from other immune cells that were used to culture the cells. "I'm afraid they've got contamination here," he said (Chase, Wall Street Journal, 9/27). Dr. Michael Selsted of the University of California-Irvine, who co-discovered defensins, also raised questions about possible contamination. However, Ho's team noted that if the defensins had come from other immune cells, they would have been found in people with HIV who had become ill. They added that defensins were found in cells taken from non-progressors that had been stored separately from other immune cells (New York Times, 9/27). Dr. Robert Gallo, a co-discover of HIV, said that even if the defensins were documented to come from CD8 cells, they cannot explain all cases of long-term non-progression. Some non-progressors' CD4 cells lack viral receptors called CCR5, while others have combinations of antigens that appear to block HIV infection. In 1995, Gallo identified another combination of chemicals produced by white blood cells called beta-chemokines that seem to block viral replication. "What's most important is that these factors vary enormously ... from one long-term non-progressor to another. There is no single answer," he said (Los Angeles Times, 9/27). He added that his team at the Institute of Human Virology has identified two new "anti-HIV substances" manufactured by the human immune system. He declined to comment further, saying that his team is writing up their results (Washington Post, 9/27).
Where to Go From Here?
Despite the skepticism, Ho and colleagues are moving ahead with research into how to use their findings on defensins to produce drugs that "mimic" their anti-HIV properties. Ho hypothesized that a "one-two punch" of defensins and beta-chemokines could help people with HIV stay healthier longer (Sternberg, USA Today, 9/27). However, Ho acknowledged that any treatment relying on defensins is still a long way off because his team has yet to identify the exact mechanism the proteins use to protect against HIV infection. He added that it will be difficult to manufacture defensins because they are composed of "long chains" of 29 or 30 "intricately folded" amino acids (Wall Street Journal, 9/27).