Mayo Clinic Team Identifies Genetic Mutation Linked to Apoptosis in HIV
Researchers at the Mayo Clinic said they have identified a gene mutation that impairs the apoptotic ability of the HIV virus. What’s more, the scientists claim that the mutation, found in a gene called Vpr, plays a “central role” in determining which patients will eventually develop full-blown AIDS.
The research, if verified, may lead to the development of molecular diagnostics and new therapeutics based on Vpr inhibitors, and may offer insight into why as many as 30 percent of patients with HIV never develop AIDS.
Led by Andrew Badley, senior author of the study, the Mayo Clinic group decided to focus on a Vpr gene linked to the HIV virus because it was known to play a role in apoptosis. Initially, the researchers found that the Vps gene in long-term nonresponders had a mutation that does not exist in so-called “typical” HIV-positive patients. In fact, the team found that the mutant gene binds to the same target as normal Vpr, but doesn’t trigger the same cell death cascade.
According to Badley, the target binds to a gene product called ANT — adenine nucleotide translocator — which is a mitochondrial transmembrane protein that “controls in part the release of proapoptotic factors from the mitochondria.”
Taking their research further, the team engineered an HIV virus and tested two versions: one that contained normal Vpr and one that contained the mutant Vpr. When they later infected cultured cells with the two strains, they came upon an interesting finding: “Lo and behold, the mutant doesn’t kill as well as the wild type Vpr,” said Badley. “That was neat to find.” The study appears in the May 15 Journal of Clinical Investigation.
These findings led Badley’s team to look at the protein product made by the mutant gene. The researchers first constructed recombinant viruses that contain either the wild-type Vpr or the mutant Vpr, then infected T-cells with them, and quantified the amount of cell death that occurred. “In those experiments, we found that the virus which contains mutant protein causes less T-cell death than does the wild-type protein,” Badley told SNPtech Reporter. “After that, we made the recombinant proteins … and treated either cells on their own with mutant versus wild-type Vpr and quantified cell death, and, similar to our infectious experiments, we found that the mutant Vpr protein does not induce cell death as readily as the wild-type protein.”
Later, the researchers injected wild-type or mutant Vpr into mice and quantified T-cell death in the mice. “What we found was that mice who received the injections of wild-type proteins had a profound depletion of T-cells, whereas mice that received mutant protein did not,” Badley said.
“By further exploring the role of Vpr we may be looking at a mechanism by which patients with long-term nonprogressive HIV disease are able to stay disease-free. That information could eventually translate into new treatments,” said Badley.
Asked whether these results may be used to develop a molecular diagnostic to help physicians determine which patients with HIV may become nonresponders, Badley said: “Absolutely, that’s a possibility. And in fact those [are the] kinds of trials we are contemplating developing.” He said this research has not yet sparked any commercial interest.
Abbott Labs Helps Artus Market, Distribute PCR-based SARS Test
Abbott Laboratories has penned a worldwide marketing and distribution agreement with German-based Artus for what is believed to be the first commercial PCR-based test to detect a form of the coronavirus linked to SARS.
Terms of the agreement call for Artus to manufacture the test, and for Abbott to market and distribute it initially for use on the Roche LightCycler thermal cycler system in North America, the UK, Germany, and Austria. In addition, within several weeks the test will be available worldwide on the Applied Biosystems ABI Prism 7000 Sequence Detection System.
Abbott will also help Artus submit the test to the US Food and Drug Administration “as quickly as possible,” and will market and distribute it through its molecular diagnostics alliance with Celera Diagnostics. That alliance, struck in June 2002, was designed to develop and market “a broad menu” of molecular diagnostics for various “unmet” undisclosed diagnostic needs.
The test, developed by Artus with the Bernhard-Nocht Institute for Tropical Medicine in Hamburg, Germany, has already been introduced by Artus in April to countries in Europe and Asia. The Abbott agreement will “supplement” this distribution network, Artus said. The test has also been provided to laboratories overseen by the World Health Organization and “other major clinical sites” conducting research on the virus.
“We believe this new test is sensitive enough to detect the virus in the early stages of infection,” said James Koziarz, vice president, diagnostic products research and development, Abbott Labs.