WASHINGTON _ The immune-suppressant drug cyclosporin mayprovide a starting point for a new class of drugs that preventreplication of HIV, researchers said Tuesday.

Stephen Goff, an investigator at the Howard Hughes MedicalInstitute and Columbia University, reported that cyclosporin disruptsthe assembly of new infectious virions from virus proteins gatheredon the T-cell surface.

This occurs because the drug bonds powerfully with a host proteinknown as cyclophilin, which is abundant in all mammalian cells.Studies have also shown that HIV-1's Gag protein _ the "engine"that assembles infectious virions _ cannot function withoutcyclophilin.

"Cyclophilin is a major virion protein in wild-type HIV," Goff said."It is incorporated at high levels _ probably higher than the level ofreverse transcriptase _ into the virion."

Goff and his coworkers decided to see how well Gag functions whenit is cut off from its supply of cyclophilin. The results were intriguing,he told the Third Conference on Retroviruses and OpportunisticInfections here.

"If we prepare virus that is either mutated so that it no longer bindscyclophilin, or grow wild-type virus in the presence of the drug _which blocks the [Gag-cyclophilin] interaction _ we produce virionparticles that are completely without infectivity," Goff said.

Heinrich Gottinger, of the Dana-Farber Cancer Institute in Boston, ina separate presentation, confirmed the findings of Goff and hiscoworkers.

Gottinger found that cyclosporin A and a similar compound that doesnot suppress immunity, known to researchers as SDZ NIM 811, bothprevent cyclophilin from being incorporated into HIV-1 virions.Without cyclophilin, Gottinger said the HIV-1 virion's infectiousnessindeed disappears.

This finding suggests that cyclophilin plays its crucial role early inthe HIV life-cycle.

Goff said the bond between the drug and cyclophilin is stronger thanthe bond linking Gag and cyclophilin.

"At equal molarity," he said, "cyclosporin can displace Gag from thecomplex."

The power of that bond is the key reason cyclosporin effectivelyshuts down graft-vs.-host disease in transplant recipients, he said.

When cyclosporin and cyclophilin together bind to a third proteinessential for signaling, the process shuts down, leaving T cells blindto signals that would ordinarily trigger an immune response.

The research marks a new approach to the development of drugsagainst HIV. It also marks a shift in the way researchers view thevirus itself.

In the past, Goff said, "most virologists conceived of the virus asbeing relatively autonomous from the host, undergoing a series ofsteps necessary for replication on their own, with very littleinvolvement from host proteins. We've come to realize over the lastfew years that that impression is completely wrong."

He said "the reality is that there are very many specific interactionsbetween viral protein and host proteins that go on inside cells." Manyof these interactions, he said, are either helpful to the virus oressential for the virus to complete its life cycle."

Most anti-HIV drug research has focused on ways to disrupt theaction of enzymes _ particularly reverse transcriptase _ within thevirus itself. But drugs able to disrupt the protein-to-proteininteractions that occur regularly during the HIV life cycle may proveequally promising.

By targeting host proteins, rather than enzymes in HIV itself, theresearchers said they believe that new drugs could, theoretically atleast, prevent viral replication without promoting the rapid cascade ofmutations that render HIV resistant to standard antiviral drugs.

The new approach has arisen out of research using a yeast two-hybridsystem, which Goff described as a particularly powerful tool formolecular biologists who study HIV.

The cyclosporin work is a prime example, he said. Goff's co-workerJeremy Luban was able to screen a million cDNAs from a human celllooking for rare members of the cDNA library that were able to bindto Gag and activate reporter genes.

They found a dozen clones _ and all of them turned out to becyclophilin, Goff said. n

-- Steve Sternberg Special To BioWorld Today

(c) 1997 American Health Consultants. All rights reserved.