Pitt School of Medicine scientists have identified drug candidates that show promise to reverse the ability of HIV to escape detection by the immune system.
The discovery reveals a potential path to eliminate the viral reservoir that cannot be cleared with existing antiretroviral drugs.
“HIV establishes a reservoir of infected cells that lay dormant even in the presence of antiretroviral therapy, hiding from immune system detection,” said senior author Thomas Smithgall, William S. McEllroy Professor of Biochemistry, Department of Microbiology and Molecular Genetics (right). “We think we’ve uncovered a key to unmasking that reservoir.”
The research centers on HIV Nef, a viral protein expressed at high levels after HIV infection. Nef can prevent the immune system from destroying infected cells by blocking or “hiding” signs of the virus on the cell surface.
Rather than pursuing a drug molecule that might only block one or two Nef functions, Smithgall and lead author Lori Emert-Sedlak (left), research associate professor of microbiology and molecular genetics, looked for a compound that would mark it for degradation in infected cells. Degrading the Nef protein would block all of its functions, including HIV infection and replication.
The resulting drug candidates—called proteolysis targeting chimeras, or PROTACs—triggered Nef degradation, which suppressed HIV replication in target cells and showed signs that the immune response could be restored.
Read more about the research in Cell Chemical Biology and in the news release.