HIV protein attacks body’s innate protection system that could prevent virus’ replication

Discovery could lead to development of protein-targeting drugs, OHSU researchers say

When HIV enters the human body, a fierce battle ensues between a ruthless viral protein and our long-misunderstood innate protection system. Ultimately, the protein seizes and destroys that system, and HIV replicates.

But Oregon Health & Science University researchers who discovered the mechanism by which this destruction occurs say our innate protection system could have a leg up in the mêlée if drugs can be developed to target the HIV-encoded viral protein.

“We’re thrilled about this,” David Kabat, Ph.D., professor of biochemistry and molecular biology at OHSU, said of the discovery.

His OHSU collaborators were: Mariana Marin, research assistant professor, Susan Kozak, senior research associate, Department of Biochemistry and Molecular Biology; and Kristin Rose, graduate research assistant, Department of Molecular Microbiology and Immunology.

The study, published Sunday in the November issue of the journal Nature Medicine, could have major implications for AIDS research. Not only does it give scientists insights into how the body’s built-in defense system works, it’s a shot in the arm for the search for more targeted, effective anti-HIV drugs.

“This is definitely relevant to drug development and pharmacology in the fight against AIDS,” Kabat said.

Kabat’s team found that the HIV-encoded protein – viral infectivity factor, or Vif – neutralizes a potent antiviral human protein called APOBEC3G that would, in the absence of Vif, inactivate HIV. Vif binds to APOBEC3G and induces its “extremely” rapid degradation, eliminating APOBEC3G from cells and keeping it from invading HIV particles where it could damage the virus’ genetic material.

APOBEC3G is a nucleic acid-editing enzyme that exists in some cells, like white blood cells, but is absent in others, such as skin cells. Cells where APOBEC3G is present are “non-permissive,” meaning they don’t allow replication of an HIV mutant which lacks a Vif gene.

When HIV or another virus is detected, APOBEC3G edits and fragments the virus’ nucleic acid.

“The body has an innate system that is capable of ridding itself of HIV,” Kabat said. “But Vif counteracts and neutralizes this defense system of the body, providing a safe nest in which HIV progeny get produced. Vif comes in and somehow recognizes this innate system. If Vif isn’t there, the progeny get destroyed during their birth.”

Kabat’s team began work on Vif in 1997 and published its first paper on the viral protein a year later. At that time, the scientists developed insights about Vif that suggested the existence of a potent antiviral defense system in human lymphocytes, and that it was Vif’s job to destroy it.

“We knew what to look for, but we didn’t know it was APOBEC3G,” Kabat said.

Scientists had known for 10 years that a relative of APOBEC3G, APOBEC1, was an nucleic acid-editing enzyme that regulates normal cellular function, but which doesn’t have an antiviral effect. Ten months ago a group of scientists in Philadelphia identified APOBEC3G as the cellular defense mechanism everyone was looking for, and the field was “cracked open.”

“APOBEC3G is related to APOBEC1. That was a clue,” Kabat said. “When this group in Philadelphia discovered APOBEC3G was involved in antiviral response, it was the first indication these nucleic acid-editing enzymes evolved to attack viruses.”

Since making its recent discovery, the OHSU team has worked to set up a system in which Vif and APOBEC3G exist in the same cell, which will let researchers examine APOBEC3G’s destruction in more detail while allowing it to be continually produced. It also is working to develop enough Vif so its structure can be studied further.

“We’re going to try to learn exactly how Vif destroys APOBEC3G in greater and greater mechanistic detail,” Kabat said.

Kabat plans to create a platform for screening potential anti-Vif drugs with the help of robotics that pull from a chemical library. The team also will work directly with drug companies on testing their products.

“The drug discovery approach is so important and we’re going to try to make a big contribution to it,” he said. “The results we have provide assays, tests and information one needs to develop drugs against Vif. These tools are useful for screening drugs, but also for testing candidate drugs.”

Kabat noted that the American Foundation for AIDS Research (amfAR) has put a premium on anti-Vif drug discovery. “It’s definitely been recognized as an important frontier in the fight against AIDS,” he said.

The study was supported by a grant from the National Institutes of Health.