Most HIV drugs act on enzymes the virus needs throughout its life cycle, but none specifically target the capsid, a shell that protects the virus' genetic material and delivers it to cells. Scientists in Australia and the U.K. have found a potential chink in this armor: a small molecule that HIV appropriates from host cells to strengthen the capsid.
HIV infects cells by invading them and replicating its genome to make new viruses. While its capsid must be strong enough to hide the virus from the immune system, it can't be so strong that it can't open, or "uncoat," to release its genome into the host cell's nucleus. This shield has been "one of the great unanswered questions in HIV biology," said Leo James, Ph.D., leader of the research team at the Medical Research Council Laboratory of Molecular Biology in Cambridge, U.K., in a statement.
Using a new type of single-molecule microscopy that allowed them to watch how capsids break apart in real time, the researchers found that the capsid binds to inositol hexakisphosphate (IP6), an acid found in mammalian and plant cells. IP6 stabilized the HIV capsids for more than 10 hours, according to the study, published in eLife. Without IP6, HIV capsids fell apart within minutes, said Till Böcking, an associate professor at the University of New South Wales.
"It's like a switch. When you bind this molecule, you stabilize the capsid, and release the molecule to open it up," Böcking said in the statement.
Other next-generation HIV treatments focus on modifying T cells to disarm HIV. Scientists from Case Western Reserve University used zinc finger nuclease gene editing to create T cells that fight HIV by disrupting its ability to invade cells, while a University of Nebraska team engineered T cells to bind to CD4, a protein that HIV exploits to enter host cells. In a similar manner, UCLA researchers developed a chimeric antigen receptor (CAR) that binds to HIV, which then triggers other parts of the CAR that become activated and kill the virus.
Future treatments could fight HIV infection by targeting IP6, specifically by triggering its "dissociation" from capsids, the U.K. and Australia teams reported. Using their microscopy technique, they plan to study a mechanism found in hexamers called the dynamic N-terminal β-hairpin. They posit that when it is closed, IP6 will stay bound to the capsid, but when open, IP6 will be free to dissociate.
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"Once we understand the molecular details of these processes, we could devise strategies to 'trick' the virus into releasing IP6 prematurely," Böcking told ScienceAlert. "Or locking it in, such that it can no longer control the correct timing for capsid uncoating."