Business Wire - Tuesday, November 24, 1998

Stanford researchers have discovered that one of HIV's requirements is a critical cellular protein called NFAT, which allows the virus to multiply in the T cells of its host.

The T cell proteins that carry out NFAT's instructions may make perfect targets for anti-HIV drugs, the researchers suggest. That's because these cellular proteins -- unlike HIV proteins -- are unlikely to mutate to escape the effects of drugs.

Traditional antiviral therapy works by interfering with protein targets that are unique to the virus, so that human cells will remain unaffected. This strategy can reduce the severity of side effects, but it also has a down side: viruses that mutate rapidly can avoid such drugs by altering the shape of their proteins.

"Each new anti-HIV drug is a step better and, one hopes, less toxic to the patient, but it's still an arms race with the virus," said Garry Nolan, Ph.D., assistant professor of molecular pharmacology. "It costs the virus nothing to evolve resistance, but it costs us many lost lives and billions of dollars. But if you can block the virus' access to something it needs, it is a long evolutionary road for the virus to reestablish access to that resource."

Nolan is the senior author of a paper on the new findings in the Nov. 25 issue of Cell.

Rest and Unrest

Nolan and senior postdoctoral fellow Shigemi Kinoshita, Ph.D., started with the observation that HIV cannot reproduce in "resting" T cells -- the majority of circulating immune cells that are quietly waiting for an invader. When resting T cells detect invaders, they start dividing to fight the invasion off. This activity also has the unwanted side effect of allowing any HIV hiding passively within those T cells to finally make copies of itself.

To find out what part of the T-cell-activation process allows HIV to reproduce, Kinoshita and Nolan looked at a critical cellular protein called NFAT, which is needed for normal early activation of T cells.

Using engineered mouse viruses, Kinoshita delivered one form of NFAT, called NFATc, to some resting T cells.

NFATc is required to activate resting T cells, but it is not sufficient by itself -- so the resting T cells with added NFATc did not divide or otherwise respond as though there were an infection.

The cells did, however, become susceptible to HIV infection.

"This is a subprogram that is not by itself sufficient to activate the T cell, but activating that subprogram allows HIV to replicate," Nolan said.

HIV can enter all resting T cells, but without active NFATc, the virus gets blocked halfway through the process of converting its RNA into DNA. HIV proteins can insert only the DNA form of viral genetic material into the human host's DNA, and only this inserted form can then produce more virus proteins and genetic material.

Although an HIV enzyme called reverse transcriptase is the primary protein required for converting RNA into DNA, it gets blocked in the absence of something provided by the T cell. That "something" may make an excellent target for a whole new class of HIV-fighting drugs, the researchers suggest.

When Nolan and Kinoshita delivered active NFATc to resting T cells, they alleviated the block, allowing HIV to reproduce. Conversely, two drugs that block the action of NFATc prevented HIV reproduction by up to 81 percent, they found. These drugs, cyclosporin and FK506, are used as immunosuppressants in patients with transplanted organs because they block T cell activation.

"NFAT itself is not the right target for new anti-HIV drugs, because blocking NFAT causes immunosuppression," Nolan said. "But NFAT is turning something on in cells that is almost certainly a good target."

Racing Toward Targets

Nolan said he and Kinoshita have rapid methods for identifying the proteins that are carrying out NFAT's orders. He believes other host cells such as macrophages, which always allow HIV to reproduce, may make these permissive proteins at all times.

Given that the targets for these hypothetical drugs remain undiscovered, the drugs will be a long time coming. But Nolan said he has confidence that this approach will be critical for developing drugs against which HIV has little ability to become resistant.

"Once the door is open toward cellular targets, it will be an all-out race to get them, especially if drugs against those targets do not block important cellular processes," he said.

Nolan and Kinoshita conducted the study with Hideto Kaneshima, M.D., a director at Systemix, Inc., in Palo Alto, Calif., and Benjamin Chen, working in the laboratory of David Baltimore, Ph.D., at the Massachusetts Institute of Technology.

Funding for the research came from the Uehara Memorial Foundation, the Irvington Institute, the Juvenile Diabetes Foundation and the National Institute of Allergy and Infectious Diseases. Nolan is a Leukemia Society of America Scholar, as well as a recipient of a Howard Hughes Young Faculty Award and a Burroughs Wellcome New Investigator in Pharmacology Award.

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CONTACT: Stanford University Medical Center Mitch Leslie, 650/725-5371 or 723-6911 (Media Contact) mleslie@leland.stanford.edu Garry Nolan, 650/725-7002 (Source) gnolan@cmgm.stanford.edu
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