Molecules Can Extend Lives of HIV Infected

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Assistant professor Gregory Weiss of the Department of Chemistry and his team of researchers have discovered small molecules called guanidine alkaloids that can expand the lifespan of a person living with HIV, a retrovirus that causes AIDS.
Guanidine alkaloids prevent a protein called Nef from binding to a cell. By attaching to cell proteins such as actin and lpk, Nef ruins a cell’s immune response by shutting down apoptosis in cells. Apoptosis allows a cell to kill itself. Without cellular apoptosis, HIV can invade the cells, replicate and cause damage.
Guanidine alkaloids attach themselves to the Nef protein, preventing the Nef protein from attaching to cellular proteins, allowing the cell to kill itself.
‘There is a fork in the road and Nef is the gatekeeper of whether someone goes on to AIDS or stays infected with HIV,’ Weiss explained.
Some people have HIV for years, while others can quickly progress to AIDS. If someone is infected with HIV and Nef proteins are not able to bind to cells, the person will go on living for a longer time without getting AIDS. In the future, hopefully people infected with HIV will not get AIDS at all. The transition from HIV to AIDS is blocked when Nef is blocked.
’50 million people in this world are infected with HIV, and to me, that’s a problem. We desperately need a vaccine for AIDS, but preventing AIDS from occurring in a HIV positive patient is a small step in that direction,’ Weiss said.
The long-term goal of Weiss’s research is to have the involvement of drug companies. The research done at UCI can only go so far, but with the involvement of drug companies, it can be possible for someone who is HIV positive to use guanidine alkaloids at home as a prescription drug.
There are inhibitors against many HIV enzymes including reverse transcriptase and protease, but only four out of 15 HIV proteins can be inhibited.
‘The fundamental goal of our research is to expand the options for treating viruses. Right now, most of the treatment options are focused on enzymes, because [scientists] are good at preventing enzymes. The goal of my research is to get us away from enzymes to focus on protein-protein interactions,’ Weiss explained.
To view these protein-protein interactions, Weiss and his researchers used a technique called ‘phage display.’ In this technique, proteins are attached to the surface of a harmless virus called a bacteriophage. Guanidine alkaloids were then added to the in vitro experiment to see the interactions.
Hundreds of thousands of compounds were screened, and the guanidine alkaloid compounds that worked were put into HIV strains.
‘The experiment that we did was the first time we looked at the inhibition of a protein,’ said UCI graduate student Allison Olszewski, who was responsible for over 90 percent of the work done in the lab. ‘Usually this experiment is used to look at proteins interacting with other proteins, but it has never been used to see proteins being inhibited.’
‘Allison was in the lab mixing the Nef and the p53, doing the experiments,’ Weiss said. ‘Day after day, she was the one who really worked hard on this project.’
Olszewski also worked with associate professor Ed Robinson, who tested drugs to look at their anti-HIV effects, and professor Larry Overman, who synthesized the guanidine alkaloids for Weiss and his researchers.
The Center for Viral Research at UCI is responsible for bringing together Weiss and Edward by setting up a network of researchers who were interested in viruses.
Weiss and his researchers are not ready to start injecting animals or humans with the guanidine alkaloids because the molecules are very toxic. The experiments were all done in vitro, which means they were done in an artificial environment, but the next step is moving into cell culture.
‘We’re trying to discover new classes of less toxic molecules and at the same time we’re trying to change around the structure of the guanidine alkaloids to make them less toxic,’ Weiss explained.
HIV, short for the human immunodeficiency virus, is known to cause AIDS. It attacks the immune system and makes the body vulnerable to infections.

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