Crucial HIV Protein Discovery Holds Promise for Powerful AIDS Drugs

by VR Sreeraman on Sep 28 2008 10:55 AM

Scientists at University of Michigan have discovered a key HIV accessory protein, called HIV-1 Nef, that thwarts the body's normal immune response - a finding that may pave the way for more powerful AIDS drugs.

While current anti-HIV drugs are life saving, they cannot root the virus out of the body. Infected cells are able to live on, undetected by the immune system, and provide the machinery for the virus to reproduce and spread.

"There's a big hole in current therapies, in that all of them prevent new infection, but none attack the cells that are already infected and hidden from the immune response," said Kathleen L. Collins, M.D., Ph.D., the study's senior author and a U-M associate professor in both internal medicine and microbiology and immunology.

She added: "People have to be on the existing drugs, and when they're not, the virus rebounds. If we can develop drugs that seek out and eradicate the remaining factories for the virus, then maybe we could eradicate the disease in that person."

HIV-1 Nef is known to keep immune system cells from doing their normal jobs of detecting and killing infected cells.

The new study shows how Nef disables two key immune system players inside an infected cell. These are molecules called major histocompatability complex 1 proteins (MHC-1) that present HIV antigens to the immune system, and CD4, the cell-surface receptor that normally locks onto a virus and allows it to enter the cell.

According to Collins. MHC-1 is similar to motion detectors on a house, which send the first signal to a monitoring station if an invader breaks in.

"The immune system, especially the cytotoxic T lymphocytes, are like the monitors who get the signal that there's a foreign invader inside the cell, and send out police cars. The 'police' are toxic chemicals produced by T lymphocyte cells, which kill the cell that harbors the invader," she said.

Nef's actions allow active virus to hide undetected and reproduce by in effect pushing the MHC-I proteins into an infected cell's "trash bin" so they fail to alert the T lymphocytes. Also, once a cell has been infected, Nef destroys CD4. thus, new virus is encouraged to spread to uninfected cells.

While Nef's activities are variable and complex, the new findings suggest that the many pathways involved may end in a final common step. That could make it possible to find a drug that could block several Nef functions.

Now, researchers are screening drug candidates to find promising Nef inhibitors. Such drugs, which are at least 10 years away from use in people, would supplement, not replace, existing anti-viral drugs given to HIV-infected people. The new drugs would target the reservoirs where the virus hides.

Collins said that in developing countries, the new drugs could have a huge impact. Today, children born with HIV infection start taking the existing anti-HIV drugs at birth.

She said that it's very hard to continue costly treatments for a lifetime. But if children could be cured within a few years, global HIV treatment efforts could spread their dollars further and be much more successful.

The study appears online in the journal PLoS Pathogens.