ZAP Gene is Crucial First Step in Cells Identifying HIV

Researchers have found how proteins specializing in identifying, capturing and destroying viruses’ genetic material latch onto foreign invaders and how some viruses, including human immunodeficiency virus, evade capture.

According to the press release, revealing the precise mechanism that makes this protein an effective antiviral in some cases is a critical first step in the path toward better methods for attacking viruses that manage to bypass it.

Researchers examined the zinc-finger antiviral protein (ZAP), which is formed by cells to restrict a virus from replicating and spreading infection. The ZAP gene is activated and produces more of the protein when cells detect a virus. ZAP then isolates the virus’s RNA from the cell’s native RNA and targets it for destruction.

The researchers examined how the protein identifies and binds to RNA to determine how HIV avoids ZAP. Using the piece of viral RNA that was genetically altered to include extra CG sequences, the researchers at the University of Michigan determined the structure of the ZAP protein bound to RNA, exposing the mechanisms that enable the protein to be so selective.

The researchers discovered that ZAP binds to the viral RNA at only 1 of the 4 “zinc fingers” on the protein that they considered potential binding sites. They further demonstrated that even a tiny change to that 1 binding site, altering just a single atom, hampered ZAP’s binding ability.

The study authors then created mutant versions of ZAP expressed in cells infected with either normal HIV or a version of the virus enriched with CG sequences. These mutant ZAP proteins were less able to recognize CG-enriched regions of the viral RNA in cells. They also exhibited increased binding to areas of the RNA that were not rich in CG dinucleotides, indicating that the alterations impair ZAP’s ability to distinguish viral RNA from human RNA.

"Natural selection appears to have shaped the ZAP protein structure in such a way to optimize the discrimination of nonself from self RNA, based on CG dinucleotide content. However, successful viruses are often one step ahead in a molecular arms race,” said Paul Bieniasz, investigator at the Howard Hughes Medical Institute and head of the Laboratory of Retrovirology at Rockefeller.

The study authors noted that their research is a crucial first step in learning how the cell eventually degrades the virus’s RNA. This study reveals how this step is executed as well as why it is not effective on HIV and other viruses that lack the CG sequence.

Reference

• New Research Explains how HIV avoids Getting ZAPped [press release]. University of Michigan News website. Published November 11, 2019. https://news.umich.edu/new-research-explains-how-hiv-avoids-getting-zapped/. Accessed November 20, 2019.