Scientists Show How Molecules Bind To HIV's Protective Shell, Blocking Infection

molekuul.be, via Shutterstock. HIV capsid.

Using a combination of biochemical and imaging techniques, scientists have demonstrated how a recently discovered inhibitory compound and two host cellular proteins help block HIV-1 replication. They found that the molecules bound to pockets present in HIV-1’s protective protein shell, preventing it from breaking apart at the crucial time required for efficient infection. According to the team, the results suggest that targeting this sweet spot could offer new avenues for therapeutic intervention. The work has been published in Proceedings of the National Academy of Sciences.

Both the structure and the life cycle of human immunodeficiency virus 1 (HIV-1), one of the causative agents of AIDS, are well described. HIV-1’s genetic material is composed of RNA, a close chemical cousin of DNA, and is packaged within a cone-shaped shell called the capsid which both protects the virus’ RNA and helps deliver it to the cells that HIV targets.

The capsid is made up of a single protein called CA which folds to form two domains, one large and one small, connected by a flexible bridge. The larger of the two domains associates with other copies of CA to form rings of either five (pentamers) or six (hexamers), whereas the smaller domain connects these rings to form the overall structure. Twelve pentamers and over one hundred hexamers come together to form the capsid.

When the virus enters host cells, the capsid needs to undergo controlled disassembly, or uncoating, before the next stages of the life cycle can ensue. This process must occur at a specific time so that the genetic material can be released and later copied, but precisely when this occurs is still up for debate, and many of the fine details of this particular stage in the viral life cycle are still hazy. However, this new study, conducted at the University of Texas Health Science Center at San Antonia offers us some new clues about the process.

Using biochemical experiments, the researchers were able to show that a recently discovered small-molecule inhibitor of HIV-1, called PF74, and two different host proteins (CPSF6 and NUP153) bind to a pocket encompassing the interface between the CA protein’s large and small domains. This was found to prevent the capsid from disassembling, keeping the viral genetic material locked away. Interestingly, this contrasts earlier work on PF74 which suggested that this inhibitor actually destabilized the capsid and made it disassemble prematurely.

The team then used a technique called X-ray crystallography to visualize the 3D structure of CPSF6 bound to the capsid, which yielded some insightful data.

“Seeing molecules in 3D is illuminating; it tells us something about their function,” study author Dmitri Ivanov said in a news-release. “We now know how PF74 and CPSF6 interact with the adjacent building blocks of the HIV-1 capsid, thus stabilizing the entire capsid structure. It tells us that these molecules bind to the capsid before disassembly, blocking viral replication.”

The researchers add that it may be possible to create mimics of the host proteins that bind even more tightly to CA, which may offer new treatment avenues. 

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