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Marc  Johnson

Researching Retrovirals

Marc Johnson, Assistant Professor, Molecular Microbiology and Immunology, UM Columbia

By Tanya Sneddon

The UMRB grant helped me build confidence, purchase tools, and fund staff to work in my lab. It gave me a kick-start.

Marc Johnson began his research career studying a rabies-like virus in fish. For a Missouri kid, who had always wanted to study marine biology, life was great. “Working with fish viruses is really cool research,” he notes, "but there are just not a lot of people doing it,” and that sense of isolation was eventually too much. “We cloned the virus’ entire genome and worked out a reverse genetics strategy. It was the breakthrough of my research, but what really bothered me was that no one really cared.” Johnson missed the collaboration, the community, and the interaction of more mainstream research life. “So I went to the absolute opposite of fish viruses, to HIV, where there are thousands of labs studying it," he recalls, "and it’s very competitive. But it’s also very interactive, which is what I wanted.”

Since that dramatic switch, Johnson has dedicated his research efforts to the study of these related human viruses. Ten years later, and now an assistant professor in the MU’s Department of Microbiology and Immunology, he and his collaborators have made great progress in understanding how the HIV virus works in order to develop new therapeutics to combat the dread disease.

HIV belongs to a unique family known as retroviruses. As Johnson explains, “there are two general kinds of viruses—the RNA viruses and the DNA viruses. You can couple them by the kinds of diseases they cause: RNA viruses are typically short-term viruses causing acute diseases such as the flu, the common cold, and Ebola. DNA viruses often are more long-term, like herpes, where, if you get it, you have it for the rest of your life.” He describes retroviruses, however, as a unique blend in between RNA and DNA: “They are technically an RNA virus, yet they are a DNA virus in part of their life-cycle. The magical thing is that they can jump between these two states. They’re like a DNA virus that can replicate with RNA strategies.”

However, retroviruses can cause long-term diseases, unlike most RNA viruses. For now, when people contract HIV, they will have the disease for life. While the scientific community has developed many extremely successful treatments for the symptoms associated with the disease, they have yet to discover a cure. Johnson explains the problem in this way: “With HIV, we have very good therapies. We have the ultimate Patriot missiles. If a missile gets shot at you, then you send up another missile to blow it up. We’ve got that. Whenever a virus is released from an infected cell into our bloodstream, we have drugs that kill that virus immediately, such that there are no new infections. After that, the few cells that were infected would die off, or the immune system would kill them.” With any other virus, that would be enough to cure the disease. But HIV is different.

“HIV just has our immune system’s ‘number,’" Johnson says. "The trouble with retroviruses, particularly with HIV, is that those last few infected cells, as long as they’re alive, just keep kicking out viruses and our immune system cannot identify them as infected cells.” Since the body is unable to kill off those last few infected cells, it is never able to rid itself of the disease entirely. Drugs known as anti-retrovirals have been greatly successful in curbing the viral replication and improving the quality of life for infected persons, but “there’s still a few infected cells, and if you take someone off their anti-retrovirals the infection comes back.”

With this perspective on HIV, Johnson has been working to further understand the structure of the virus and the function of each component. His hope is that if they “can mess it up at the right step, it might throw the virus off its game and allow the infected cells to be exposed as infected,” thereby potentially eliminating the HIV infection. There are three key structural components of the HIV virus, all of which function like the parts of a missile. The protein Gag is the structural protein that forms the actual physical virus particle that moves around and attacks things. It’s like the missile shell. There’s also a protein called Pol, which is like the payload of a missile, responsible for replicating the genome. And a third protein, Env, determines which cell the virus is going to attack next, like the trajectory system of a missile. “Mostly I study Gag,” says Johnson, “how it assembles itself, how it tricks the cell into helping it assemble a virus, and how the other components of the virus get to the right place.” The sheer probability that all these components will find each other is daunting, like “three people in the state of Missouri finding their way to the same cornfield.” This is just one of the many puzzles Johnson hopes to answer through his research.

With a complete grasp of the structure of the HIV retrovirus, several things will be possible, Johnson suggests. First, new therapies will be developed, new missiles to shoot in defense as the HIV virus sends up its own. “There are four, maybe five steps of the HIV life-cycle that we can target,” he explains, “but we’re learning that there are more ways to block it and plenty more reasons to continue to improve the therapies.” The second projected advance is in the area of gene therapy. “There are diseases like Cystic Fibrosis,” he notes, “where we know people are missing just one gene in their cells, and if we could just treat them with the virus (use the virus to reintroduce the gene), it would be there forever.” Or, he adds, they could cause tiny mutations in the genomes and then insert them into a human host cell.

Finally, Johnson believes that understanding these viruses will lead to a more informed general perspective on how the human cell works: “Almost everything we know about modern molecular biology—how DNA replicates, how RNA is transcribed, how RNA is processed, how gene regulation occurs—came from studying viruses. It’s pretty remarkable, and there’s clearly a lot about it that we don’t know yet,” he admits. But he has noticed one dramatic development: that progress in this line of virus research draws far more attention than his earlier studies of fish.