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Scientists at two American institutions have discovered a way of replicating the HIV-1 virus, ending a significant scientific challenge that has slowed down research on the virus.
Since the HIV-1 virus won't replicate in monkey cells, researchers have to use a monkey virus--known as SIVmac, or the macaque version of simian immunodeficiency virus--to test possible therapies and vaccines in animals. However, vaccines and therapies that are effective on SIV don't necessarily equal human success.
By using a combination of genetic engineering and forced adaptation, scientists at Rockefeller University and the Aaron Diamond AIDS Research Center, both in New York City, have created a version of the AIDS virus that replicates vigorously in both monkey and human cells--a breakthrough that researchers say has the potential to revolutionize vaccine research.
In a paper published in the October 6 issue of Science, Paul Bieniasz, associate professor and head of the Laboratory of Retrovirology, explains how he and his colleagues maneuvered around the intrinsic immunity of primate cells by replacing the few parts of the human virus responsible for blocking its replication in monkey cells with components from SIV.
"Overall, the virus is a mixture of engineering and forced evolution," Bieniasz said in the Science article. "It sounds simple in theory, but it took us two years to do."
Bieniasz and Theodora Hatziioannou, the paper's first author and a research scientist in the lab, had to overcome two key obstacles: The first was a protein called TRIM5 that in monkeys recognizes the outer shell, or "capsid," of HIV-1 but not that of SIV.
By substituting the capsid region of the HIV-1 genome for the monkey virus and then selectively growing the viruses that replicated most vigorously over several generations, Hatziioannou created an HIV-1 mutant that could get past the monkey cells' TRIM5 recognition.
Another feat of engineering was required to get around the second obstacle: APOBEC proteins produced by a host typically force invading viruses to mutate to such an extreme that they cannot survive, but HIV-1 uses a protein called Vif to destroy APOBEC proteins, preventing any attack.
APOBEC proteins in monkeys, however, aren't susceptible to the human virus's Vif. So Hatziioannou did another switch--the SIV Vif gene for the HIV gene. Then there was another round of forced adaptation to create viruses that would multiply with vigor.
The scientists named their end result simian tropic HIV (stHIV)--a form of HIV-1 that is only different from the original by about 10% but still effectively infects primate cells and can be used to test potential therapies and vaccines.
Bieniasz said in the article, "If we can make this virus work in animals the way it works in tissue culture, it will likely change the way that AIDS vaccine and therapeutics research is done." (The Advocate)