After penetrating its target T cell, an AIDS virus conscripts one ofthat cell's own proteins, cyclophilin, to help HIV construct itsprogenies' virions. These are the viral particles that the retrovirusneeds in order to replicate, and infect new cellular victims.Cyclophilin perpetrates its fifth-column subversion in aid of theinvading virus by binding to the HIV-1 Gag _ the polyproteinprecursor of the virion's structural proteins.
What cyclophilins do in normal life is largely unknown. They seemto play a part in host-protein folding, and in protecting cells fromheat shock. They also serve as target for cyclosporin A, a majorimmunosuppressant drug that has much improved the post-operativeprospects of organ transplant recipients.
This coincidence suggests the intriguing possibility that inhibitingcyclophilin in the T lymphocytes that HIV attacks could curb theviral onslaught on those immune-system host cells. The suggestionarises from two back-to-back but independent papers in the currentissue of Nature, dated Nov. 24.
The separate research reports bear almost identical titles. One, by agroup at Columbia University College of Physicians and Surgeons inNew York, describes "Specific incorporation of cyclophilin A intoHIV-1 virions." The other, from Harvard Medical School, deals with"Functional association of cyclophilin A with HIV-1 virions."
Both groups report that, using cyclosporin A analogs, they inhibitedthe association of cyclophilin with HIV-1 virions in a dose-dependent manner. This effect, the Harvard team noted, was"accompanied by reductions in virion infectivity, indicating that theassociation is functionally relevant."
Organ Transplantation Mainstay To The RescueWhat's more, they showed that a non-immunosuppressive analog ofcyclosporin, supplied to them by the Sandoz Research Institute inVienna, Austria was equally effective in preventing cyclophilin fromabetting HIV-1 replication. But it was totally inactive against asimian immunodeficiency virus (SIV) closely related to human HIV-1, but which does not incorporate cyclophilin A.
The Columbia team reported similar infectivity-inhibiting results with cyclosporin A analogs, against HIV-1 but notSIV. These findings, it concluded, "indicate that the interaction ofGag [HIV's structural polyprotein] with cyclophilin A is necessaryfor the formation of infectious HIV-1 virions."
Columbia's Jeremy Luban, first author of his group's Nature paper,directs an independently funded AIDS virology lab at the university.He and his group have obtained more mutants confirming the paper'sreport that mutations in Gag disrupted the cyclophilin interaction,Luban told BioWorld Today. "The more data you have," he said,"the stronger the case you can make."
They are also trying to identify viruses resistant to cyclosporin, andothers that require the same interaction. "So far, we've looked at anumber of SIV isolates, and have not yet found any that interact," hesaid. Finding one or more, Luban pointed out, "might provide uswith a useful primate model for studying drugs -- perhapscompounds that would work better than cyclosporin -- to block thisinteraction."
These two separate but equal reports "identify, for the first time, ahuman protein that promotes the formation of infectious HIV-1virions," states an editorial in the current Nature. Its authors, at DukeUniversity School of Medicine, are prominent in the same field ofAIDS virology.
Therapy's Glass Half Empty And Half FullYet, as for the therapeutic potential of using a cyclosporin derivativeto block cyclophilin in treating AIDS, the commentators "areinclined to be pessimistic." For one thing, any such long-termtreatment "would probably result in significant toxicity." Foranother, "HIV-1 may well be able to mutate to a cyclosporin-resistant form."
On the bright side, the editorial concludes that such mutants might"help answer the intriguing question of why HIV-1 is apparentlyunique among retroviruses in requiring this particular [cyclophilin]form of host-cell assistance."
Columbia's Luban and AIDS virologist Heinrich Gottlinger,principal author of the Harvard paper in Nature, concur with both thepessimism and the optimism of the commentators. "Right on themark!" said Luban.
"They may be right," Gottlinger told BioWorld Today. "We have notbeen involved in the clinical potential in any way. Our interest wasmainly to study this surprising interaction with this host-cellprotein."
He explained that "The clinical perspective is really being followedby Sandoz. They got interested in those drugs because they notedeven earlier than me that they have anti-HIV activity." Gottlinger is amember of the Harvard Committee on Virology, and is a principalinvestigator at the Dana-Farber Cancer Institute's retrovirologydivision.
Since submitting his paper to Nature, he and his associates have"almost proved that the necessity for this retroviral-cyclophilininteraction is conferred by the capsid domain of the HIV-1 Gagprecursor." n
-- David N. Leff Science Editor
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