On trips to the zoo, small kids tend to crowd into the monkey house - perhaps from a feeling of kinship. One cage in particular features a bunch of round-headed animals 10 to 20 inches long, plus a bushy tail with dense, soft grizzled gray or brown fur. It gets its name from its large, yellow-brown eyes surmounted by white markings that separate three dark bands on the crown. The sign on the cage reads, "Owl Monkey (Aotes trivirgatus), also known as durukuli.' They belong to the Cebidae, or New World monkeys."

Molecular virologist Paul Bieniasz has a soft spot for owl monkeys. "One of the most interesting species in our laboratory," he observed, "are owl monkeys. They are not naturally infected by HIV or SIV [simian immunodeficient virus]. In that owl species," he added, "we've found that cyclophilin, associated with viral capsid, confers sensitivity to this cellular inhibitor in owl monkeys - completely the opposite of what happens in humans.

"One of the two species we studied," Bieniasz continued, "were rhesus monkeys - the most common types used in HIV vaccine research. Macaques are an Asian species that are not, it appears, naturally affected by HIV or SIV. But our rhesus monkeys did become infected in a U.S. primate center.

"And finally we've experimented with African green monkeys (AGM). They're naturally infected at quite high frequency. And in neither Mac nor AGM did the presence or absence of cyclophilin A appear to matter. So the inhibitors present in those two primate species recognize and block the HIV capsid, irrespective of the presence or absence of cyclophilin. All there monkeys are resistant to HIV-1."

Bieniasz is senior author of an article in Nature Medicine, released online Aug. 3, 2003, and titled "Cyclophilin A modulates the sensitivity of HIV-1 to host restriction factors." (It's scheduled for September print publication.) Bieniasz's joint appointment is at the Aaron Diamond Cancer Center and as staff scientist at the Rockefeller University in New York.

Evil Viruses Coax Cyclophilin To Help It Replicate

"For many years now," he observed, "we've known that the capsids of HIV-1 bind to a host-cell protein called cyclophilin A. It's been very unclear why the virus would do that, but it is known that this interaction between the capsid and cyclophilin A does facilitate replication of HIV-1.

"What we reported in this Nature Medicine paper," he told BioWorld Today, "is that what the cyclophilin A protein actually does is defend the AIDS virus against inhibitors - natural endogenous cellular inhibitors. So in human cells," he explained, "the ability of the viral capsid to bind cyclophilin A is a mechanism that the virus uses as a defense against the cellular inhibitor in humans - which is Ref-1.

"In certain species of monkeys," Bieniasz went on, "the interaction between capsid and cyclophilin actually has precisely the opposite effect. It exposes the virus to inhibitors - in particular, monkey species. In other primates, the presence or absence of cyclophilin A bound to the viral capsid appears to have no effect. Now we think," he continued, "that the phenotypes we've observed in monkeys are essentially evolutionary accidents, and that the meaningful phenotype is what happens in human cells, because obviously the virus is adapted to grow in humans, not in monkeys.

"For instance, many monkey cells resist infection by HIV-1. In our [Proceedings of the National Academy of Sciences] paper last year, we showed that resistant phenotype was dominant in monkeys. We now know that cyclophilin binding to the viral capsid has very dramatic effects on the recognition of the HIV-1 capsid by the human cellular inhibitors. (See BioWorld Today, Aug. 1, 2002.)

"In terms of implications developing new therapies or new animal models," he suggested, "one could conceive - although it would be very difficult - of trying to design or screen for molecules that expose the HIV-1 capsid to the cellular inhibitors that exist in human cells."

Shifting gears, Bieniasz turned from cyclophilin to cyclosporin. "Cyclosporin itself is a molecule that binds to cyclophilin," he noted. "It's used clinically as an immunosuppressant. Obviously one would not want to use it in terms of modulating the human immune system. But at least in vitro, in cell culture, if we use cyclosporin we can expose the HIV-1 capsid to the cellular inhibitors present in human cells. Because what cyclosporin does is strip off the cyclophilins from the HIV-1 capsid, which is now at least partially sensitive to the natural inhibitory action of Ref-1, present in human cells."

Molecules Seek Niche For Treating HIV Infection

"Now, cyclosporin," he added, "isn't the ideal drug to do this with human patients. You need quite a high concentration in order to achieve this effect. But it's at least conceivable that more potent molecules that act in the same way might one day find their niche as treatment for HIV-1 infection.

"It's a little bit unclear," he noted, "what our specific journal article means in terms of animal models for HIV and SIV. But in an overall sense, engineering the virus to avoid these restriction factors in monkey cells might one day give us an HIV-1 strain that can grow in monkeys. That would really have impact on the way vaccines are conducted. And, potentially, it could facilitate preclinical evaluation of novel therapies.

"The patterns of resistance that we see in this ongoing work do not fit any simple evolutionary model. We're simply going to have to discover what these factors are, to find out whether they come from a single ancestral resistance gene or have arisen separately in different primate species. We're now doing genetic screens for these resistance factors. We don't have them yet.

"We're working in ongoing research to try and obtain an HIV-1 strain that can infect nonhuman primates. This is based in part on the knowledge that one of the reasons you can't infect monkeys with HIV-1 is because of its cellular inhibitors, specifically Ref-1 inhibitors. They exist in virtually every primate species that we've looked at. And in nonhuman primates, they block HIV-1 infection irrespective of whether cyclophilin is present."