Biomedical Frontiers: Winter 1995, Vol.2, No.2
New Achilles' Heel For AIDS Virus

Columbia scientists have discovered a potential Achilles' heel in the AIDS virus's ability to infect cells. The researchers found that to be infectious, HIV-1 must contain a protein it takes from human cells, and drugs that block the protein's incorporati on can cripple the virus. Published in the Nov. 24, 1994, issue of Nature, the findings offer an innovative approach to the development of future AIDS treatments.

"Our work suggests a completely new target for the development of drugs that could block HIV-1 infection," says Dr. Jeremy Luban, assistant professor of medicine and lead author on the paper. "Therapies that stop incorporation of the host factor protein i nto HIV-1 could incapacitate the virus."

In the article, Dr. Luban and his team report that to be infectious in cell culture, HIV-1 must incorporate a human protein, called cyclophilin A, into mature virus. Without cyclophilin A, the disabled HIV-1 cannot infect cells. Certain drugs also prevent cyclophilin A uptake and make the virus unable to kill cells in culture.

HIV-1 is the major strain of virus that causes AIDS. During replication, the virus's major structural protein, Gag, snatches the common cellular protein, cyclophilin A, from inside infected cells and puts it into viral particles.

"Agents that specifically interfere with the interaction of cyclophilin A and Gag would be candidates for new antiviral therapies," says Dr. Luban.

Dr. Luban's group shows cyclosporin A can prevent cyclophilin A inclusion into the virus and render it uninfectious. Cyclosporin A, an immunosuppressant used to prevent tissue rejection in organ transplantation, inhibits Gag and cyclophilin A binding.

"The problem, though, with cyclosporin A as a potential treatment for HIV-1 infection is that you would be giving an immunosuppressant to an immunocompromised person. Also, our findings suggest high and potentially toxic doses would be necessary," says Dr . Luban.

But in an article in the same issue of Nature, researchers from Boston's Dana-Farber Cancer Institute report cyclosporin A-related compounds without immunosuppressant activity also stop viral replication.

"We have similar unpublished findings with cyclosporin-like agents," says Dr. Luban. "More research is needed to understand if these other agents could have anti-HIV effects clinically."

Using molecular biological tools, the Columbia researchers identified the region on Gag that allows it to bind cyclophilin A. They altered the Gag protein so one amino acid (proline) at position 222 was different. This mutated Gag no longer bound cyclophi lin A and was not infectious.

click here for large image (72k)

The researchers hypothesize cyclophilin A may play an enzymatic role for the virus. Cyclophilin A is an enzyme-a peptidyl-prolyl isomerase-that changes the orientation of prolines in proteins.

"By regulating the proline orientation on the Gag protein, cyclophilin A may play a role in maintaining the structural integrity of Gag. Without it, Gag may not fold properly," suggests Dr. Luban.

The finding is the first example of HIV-1 specifically including a host factor into its viral particles to make them infectious, says Dr. Luban. Although HIV-1 picks up host proteins from infected cell membranes, Dr. Luban says, there is no clear evidence of specificity in this process as there now is with cyclophilin A.

More research will clarify further the role cyclophilin A plays in Gag function and determine if the interaction plays a role in disease.

The Nature study extends the team's work from test tube experiments, published in the June 18, 1993, issue of Cell (See Frontiers Vol. 1, Fall 1993, p. 2), to cell and viral cultures .