New research by scientists at the University of Michigan could lead to the development of drugs to combat HIV/AIDS in the next decade. These new findings, published online in the August 2008 issue of Public Library of Science (PLoS) Pathogens, provide enhanced understanding of a key HIV accessory protein that thwarts the body’s normal immune response to the virus.
The protein, HIV-1 Nef (negative factor), prevents immune system cells from detecting and killing infected cells, as they would normally do. In the study, lead author Kathleen Collins, MD, PhD, and her team found that Nef disables two key immune system players inside an HIV-infected cell. These are molecules called major histocompatability complex 1 proteins (MHC-1) that present HIV antigens to the immune system to provoke a response, and CD4, the cell-surface receptor that locks onto a virus and allows it to enter the cell.
Nef hinders MHC-1 by gluing the proteins together in an abnormal way. Without MHC-1 proteins to alert the immune system about HIV, the infected cell is hidden from immune response. And once a cell has been infected, Nef destroys CD4, taking the receptor off the cell surface. The lack of CD4 receptors on the cell surface means that viral particles outside the cell can then infect other cells, spreading HIV instead of reinfecting the same cell.
Nef’s activities are varied 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 develop a drug that could block several Nef functions. If Nef is blocked, HIV-infected cells could become targets of the immune system, potentially causing them to be cleared.
“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 Collins, an associate professor in internal medicine and microbiology and immunology at the University of Michigan in Ann Arbor. The team hopes that their findings will lead to new drugs that resolve HIV/AIDS in those affected.
“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,” she says.
Collins’ lab is now 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 antiviral drugs given to people living with HIV/AIDS. The new drugs would target the reservoirs where the virus hides.