“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,” says 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.
In people infected with HIV (human immunodeficiency virus), the virus that causes AIDS, there’s an unsolved problem with current anti-viral drugs. Though 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.
“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,” Collins says.
Collins and her team show 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.
Collins likens MHC-1 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,” she says. “The ‘police’ are toxic chemicals produced by T lymphocyte cells, which kill the cell that harbors the invader.”
By in effect pushing the MHC-I proteins into an infected cell’s “trash bin” so they fail to alert the T lymphocytes, Nef’s actions allow active virus to hide undetected and reproduce. Also, once a cell has been infected, Nef destroys CD4. The result is that this encourages new virus to spread to uninfected cells.
Nef’s activities are variable and complex. But the research team’s 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.Implications:
In developing countries, the new drugs could have a huge impact, Collins says. Today, children born with HIV infection start taking the existing anti-HIV drugs at birth. 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, she says.
Additional U-M authors are first author Malinda R. Schaefer, Ph.D.; Elizabeth R. Wonderlich, Jeremiah F. Roeth and Jolie A. Leonard.
Funding for the research came from the National Institutes of Health and U-M.
Citation: PLoS Pathogens, doi:10.1371/journal.ppat.1000131
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