Mifepristone, a compound that inhibits pregnancy (by blockingprogesterone) also inhibits the AIDS virus, by blocking the productof an HIV-1 gene called vpr.
Better known as RU-486, the chemical abortifacient mifepristone,prevents Vpr, the 96-amino-acid, 15-kilodalton protein that vprencodes, from setting up HIV's target cells to replicate the virusrather than themselves. (See BioWorld Today, Aug. 18, 1994, p. 1.)
Scientists at the University of Pennsylvania have found anotherprotein, rip-1, which goes along with Vpr to bind their glucocorticoidsteroid hormone receptor. This complex then enters the victimizedcell's nucleus, where it activates the viral transcription process. Theynow propose that "Anti-glucocorticoid agents could abrogate theabove-described Vpr functions, suggesting that this pathway could berelevant for limiting HIV infection."
Suiting their actions to these words, molecular virologist DavidWeiner and his co-authors report testing such inhibitors, notablymifepristone, in today's Proceedings of the National Academy ofSciences (PNAS), dated April 11. Their paper is titled, "Theglucocorticoid receptor type II complex is a target of the HIV-1 vprgene product."
They located their rip-1 protein in monocyte/ macrophages obtainedfrom a healthy HIV-1 seronegative donor, as well as in otherimmune-system cells that are the first victims of AIDS virus attack.
"We observed," the article said, "that mifepristone could inhibit boththe Vpr-induced glucocorticoid translocation event [into the cellnucleus], as well as the Vpr-induced enhancement of viralreplication."
Weiner surmises that Vpr's connection to the receptor pathway mayrelate to "several pathologies observed in AIDS patients," notablyimmunosuppression, apoptosis in thymocytes and T cells, muscle-wasting and susceptibility to fungal infection. Interference with thepathway by mifepristone or other inhibitors, he suggested, "may haverelevance for the clinical management of HIV infection."
Discovery by Weiner and his team of the Vpr pathway is beingannounced today by Apollon Inc., of Malvern, Pa., which holdsexclusive licenses from the university for developing drugs based onthe Vpr/rip-1/glucocorticoid-receptor pathway, on which patents arepending.
Trials Are 1 To 2 Years Away
Apollon, said its president and CEO, Vincent Zurawski, Jr., "iscurrently doing drug evaluations with prospective commercialpartners, major pharmaceutical corporations. He told BioWorldToday, "We're in the process of really making a decision based onpotential clinical outcomes of whether or not to move to a clinicaltrial with an anti-glucocorticoid-II antagonist. I think we'll make that decision onestimates of what the probable detrimental effect to the patients mightbe versus positive benefits."
Initiating such a trial, Zurawski estimates, "with the appropriatepartner, we're probably looking at a one- to two-year time frame."
Weiner told BioWorld Today why he has "big reservations" aboutthe use of mifepristone as drug of choice in disrupting the pathway:"The glucocorticoid pathway," he said, "is very important in thebody. It's regulated by adrenal gland production of cortisol. Thefeedback is such that if you suppress the pathway, the adrenals mightjust make more cortisol, and hurt the patient."
He expresses "an enormous fear" that unless the first studies are doneextremely carefully, and really closely monitored," people lacking thenecessary skills, but avid for new AIDS treatments, "might just get ahold of RU-486, which is going to be available, and it could have theopposite of the desired effects."
Weiner and Apollon have talked with the clinical trials and drugdevelopment branches at the National Institutes of Health.
Virologist Carl Dieffenbach, acting associate director of the basicscience AIDS program in the National Institute of Allergy andInfectious Diseases, told BioWorld Today: "Any time a new pathwayinvolved in HIV gene regulation is uncovered, it offers opportunitiesfor therapeutic vaccine discovery to the biomedical world.Biotechnology companies," he added, "are very good about takingfindings like this and jumping on them, determining immediately, orwithin a matter of months or years, the feasibility of inhibitors in thispathway. We'll never know until we do a clinical trial."
Dieffenbach added a caveat: "From the standpoint of biotech, theonly other thing to be aware of is, like all pathways, this one is cell-type specific Some cells that play a role in HIV pathogenesis may nothave it, but others do.
"It's a real opportunity for biotech," he concluded. "Our ultimategoal, because of the drug-resistance issue, is to find drugs that hitdifferent targets within HIV. And the more targets we have, the morechances we have to really cripple the virus." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.