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

Investigators from the University of Michigan (U-M) have shown the precise mechanism that makes this protein an effective antiviral in some cases, which 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. This 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 study’s purpose was to determine how HIV avoids ZAP. The researchers examined how the protein identifies and binds the RNA.

Using a piece of viral RNA that was genetically altered to include extra CG sequences, the researchers at U-M 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 as 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.

They 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 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 the 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, the authors wrote.

Reference
  1. 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.