15 May 2002 10:00 GMT

by Julie Clayton, BioMedNet News

No fewer than four different HIV-blocking agents have now received clearance to enter phase III clinical trials involving thousands of women, for preventing sexual transmission of the virus. But some researchers are warning that three of the products are too similar to warrant simultaneous trials until more is known about their action, delegates heard yesterday at Microbicides 2002 in Antwerp.

The three products are Carraguard, a seaweed extract; PRO 2000, a naphthalene sulfate polymer; and Dextrin-2 Sulfate. They are all polymers containing negatively charged molecules that block electrostatic attraction between HIV's gp120 envelope protein and target cells.

In the vagina and rectum these targets are likely to be both epithelial cells and immune system cells, such as T cells, macrophages and dendritic cells. The products also hold promise against other sexually transmitted infection, including herpes virus and chlamydia.

The fourth agent is BufferGel, which maintains the normal acidic pH of the vagina against the onslaught of alkaline semen, and is toxic to both HIV virus and sperm.

New laboratory findings, however, are revealing that these agents may not be as effective against the types of HIV most often associated with initial infection. The results are leading some researchers to question the rationale for planning so many trials at once.

"I'm concerned about the wisdom of doing multiple simultaneous efficacy trials of sulfated polysaccharides," said John Moore, of Cornell University in New York. "If one of them fails, probably all of them will fail, because their principle of action is the same."

Early tests of the compounds were in laboratory-adapted strains from individuals with late-stage disease. These "R4" variants prefer to bind to a target cell protein called CXCR4, which is normally a receptor for chemical attractants called chemokines, before fusion with the target cell membrane. For reasons that are poorly understood, variants that dominate the initial stages of infection bind instead to the CCR5 chemokine receptor.

New research by Quentin Sattentau at Imperial College School of Medicine in London, and other groups, is now revealing that polyanion sulfates similar to those in clinical trials are less effective against R5-binding viruses than their R4 counterparts.

His team found by in vitro affinity binding assays that the prototype compound dextran sulfate had a lower binding affinity for R5 than R4 viruses, with none detected for two particular R5 variants. Moreover, the compound failed to prevent infection of cultured target cells by some R5 isolates, compared with its action on R4 variants.

"It's a bit worrying," he said.

The findings confirmed modeling predictions showing that R5 viruses have less positive charge on the gp120 surface compared with that of R4 viruses.

Sattentau admits, however, that the polyanion sulfates may still be effective in the clinic, as they have higher binding affinities than the dextran sulfate used in his laboratory. "There may still be sufficient sensitivity for us to see efficacy in vivo," he told BioMedNet News.

The full range of compounds now needs to be assessed against a wide panel of different primary isolates of HIV, he says. And with the first animal model involving an R5 strain developed just last year, it should now be possible to test these predictions in vivo, Sattentau adds.

"We all predict that R5 viruses will be less sensitive to polyanion sulfates but there's actually very little data out there," he noted.

Ultimately, the answer may be to add together these types of compounds with agents that act differently, and against R5 viruses, Sattentau suggested.

Combinations are the most likely way forward, agrees Jonathan Weber, who leads HIV clinical trials at Imperial College, and has spent the past 14 years conducting tests with Dextrin-2 Sulfate.

"The beauty of dextrin sulfate is that it's completely safe: you can put it in in very high concentrations and there's no toxicity," Weber said. "But even if you use a very high concentration you're asking an awful lot to try to prevent interaction of all virions that are going to be present in an ejaculate."

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See also:
The scope and potential of vaginal drug delivery
[Research Focus]
Kavita Vermani, Sanjay Garg
Pharmaceutical Science and Technology Today, 2000, 3:10:359-364

HIV cast adrift
[In brief]
Stephanie de Bono
Trends in Biochemical Sciences, 2001, 26:9:533

Depleting cholesterol to make sex safer
[News]
Martina Habeck
Drug Discovery Today, 2001, 6:19:973-974
 

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