How HIV dodges our immune defenses

New research reveals how a protein that specializes in killing off invading viruses latches on to attackers, as well as how some viruses like HIV evade capture and death.

Humans have evolved dynamic defense mechanisms against the viruses that seek to infect our bodies—proteins that specialize in identifying, capturing, and destroying the genetic material that viruses try to sneak into our cells.

Revealing the precise mechanism that makes the protein, called ZAP (short for zinc-finger antiviral protein), an effective antiviral in some cases is a critical first step in the path toward better methods for attacking viruses that manage to dodge it.

Cells make ZAP to restrict a virus from replicating and spreading infection. When cells detect a virus, the ZAP gene turns on and produces more of the protein. ZAP then singles out the virus’s genetic material, RNA, from the cell’s native RNA and targets the viral RNA for destruction.

The researchers wanted to determine how ZAP recognizes the virus’s genome and how some viruses avoid it.

ZAP vs. HIV

A previous study revealed that ZAP grabs onto only one specific sequence of neighboring nucleotides (the building blocks of DNA and RNA): a cytosine followed by a guanine, or a CG dinucleotide. Human RNAs have few CG dinucleotides, and HIV RNA has evolved to mimic this characteristic.

“The main motivation for the study was, ‘How does HIV avoid this antiviral protein?'” says co-lead author Jennifer Meagher, a researcher at the Life Sciences Institute at the University of Michigan. “And because we’re structural biologists, we wanted to determine how ZAP ‘sees’ a CG dinucleotide—and how, structurally, it binds the RNA.”

Using a piece of viral RNA that researchers genetically altered to include extra CG sequences, Meagher and her colleagues 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 one of the four “zinc fingers” on the protein that they considered potential binding sites. They further demonstrated that even a tiny change to that one binding site—altering just a single atom—hampered ZAP’s binding ability.

A ‘molecular arms race’

Working in cells, researchers found similar results when they altered ZAP’s composition. They created mutant versions of ZAP that cells infected with either normal HIV or a version of the virus enriched with CG sequences expressed.

The mutant ZAP proteins hard a harder time recognizing 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,” says Paul Bieniasz, an investigator in the Howard Hughes Medical Institute and head of the Laboratory of Retrovirology at Rockefeller University . “However, successful viruses are often one step ahead in a molecular arms race.”

“This is the crucial first step in a complicated story of how the cell eventually degrades the virus’s RNA,” says Janet Smith, an research professor at LSI and a professor of biological chemistry at the University of Michigan Medical School. “And now we know how the step is executed, and why it is not effective on HIV and other viruses that lack this CG sequence.”

The paper appears in the Proceedings of the National Academy of Sciences.

The research was done through the Center for HIV RNA Studies and received support from the National Institutes of Health, Howard Hughes Medical Institute, Michigan Economic Development Corporation, and the Michigan Technology Tri-Corridor. X-ray crystallography data came from the US Department of Energy’s Advanced Photon Source at Argonne National Laboratory.

Source: University of Michigan

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