A human antiviral defense factor that successfully fights off infection by a leukemia virus can also prevent infection by HIV-1, the most common HIV virus. But HIV-1 gets around this defense by shielding itself with another human protein. The new findings, by Dr. Jeremy Luban, associate professor of microbiology and medicine, along with Dr. Stephen Goff, Higgins Professor of Biochemistry and Molecular Biophysics, and colleagues at The Rockefeller University were published in the September issue of Nature Medicine.
The viral defense factor, called Ref-1, was discovered only a few years ago when it was found to block infection of human cells by a particular animal retrovirus. Although Ref-1's gene has not been identified yet, its antiretroviral activity resembles defenses in non-human primates and mice. All three defenses attack the virus after it has entered the cell but before it integrates its genome into the host cell's DNA to complete infection.
The new findings show that Ref-1, the human defense factor, is also capable of attacking HIV-1 in addition to the animal viruses. But Ref-1 could only attack HIV-1 when the researchers prevented the virus from shielding itself with another human protein. That protein, called cyclophilin A, attaches to the virus's capsid, a coat that surrounds the viral genome, and protects HIV-1 from Ref-1's antiviral activity. When HIV-1 was cultured under conditions where cyclophilin A was disrupted, Ref-1 inhibited infection.
Molecules that compete with cyclophilin for binding to capsid inhibit HIV-1 in the laboratory and could potentially be effective as AIDS therapies. Cyclosporine, an anti-rejection drug used to prevent rejection of organ transplants, prevents cyclophilin binding but is unsuitable for patients because it weakens the immune system. Non-immunosuppressive analogues of cyclosporine are effective at inhibiting HIV-1 and are more appealing as drug candidates.
Other targets for new HIV therapies may also materialize when researchers find the Ref-1 gene and understand how the defense attacks the virus. The defense may work similarly to another antiretroviral protein discovered earlier this year, which mutates the HIV-1 genome. Dr. Luban's lab is now racing to identify the Ref-1 gene so these questions can be answered.
Additional potential for the development of new HIV therapies and vaccines may lie in the researcher's second discovery, which explains why the virus cannot infect monkeys. Because non-human primates aren't infected by HIV-1, scientists can only study the pathology of the disease in humans. Or they study monkeys infected with a simian immunodeficiency virus.
"Consequently, how the virus escapes control of the immune system is still a matter of great controversy," Dr. Luban says. "That's critical for the development of a vaccine. The world critically needs a vaccine, and without a good animal model attempts to rationally design one are severely hampered."
The new research shows that HIV-1 fails to infect non-human primates because a defense similar to human Ref-1 successfully attacks the virus.
Curiously, the defense system succeeds in monkeys for the same reason it fails in humans. In monkeys, cyclophilin attachment to the capsid helps the defense proteins thwart HIV infection, while in humans, cyclophilin attachment thwarts the defense proteins. A badly needed primate model for AIDS, therefore, could possibly be developed by preventing cyclophilin from binding the HIV-1 capsid or by disabling the monkey's defense proteins.