Just maybe, a CU professor is on to it
By Leigh E. Rich
More like a “James Bond plot” than stereotypical science, CU Health Sciences Center Assistant Professor of Medicine, Dr. Leland Shapiro, has “discovered a candidate” that could lead to a pharmaceutical treatment for AIDS, an immunological disease caused by the human immunodeficiency virus (HIV).
When he began his research, and even now after publication of his results in the Federation of the American Societies of Experimental Biology Journal this month, Shapiro says the reaction he receives from colleagues remains at the level of the incredulous. “It’s like saying sugar treats HIV,” he explains, tongue in cheek.
The potential drug will be based off of Shapiro’s work with alpha-1-antitrypsin (AAT), a naturally occurring protein in human blood which appears to prevent HIV from entering human cells. If the virus can’t gain access to a host cell, it cannot not replicate or, thus, cause AIDS.
“What we have shown is that AAT inhibits HIV,” he says.
Based on laboratory results only—it could take five more years before a drug is developed and tested in human subjects—even Dr. Shapiro approaches his overwhelming results with “guarded optimism,” though not out of disbelief. Ruminating the possible ramifications of the findings, he knows even his preliminary results could create false hope for AIDS patients nationwide as well as a run on AAT supplements produced by the pharmaceutical industry to treat people who are genetically AAT deficient.
“It’s still laboratory stuff,” he warns. “We don’t know if it will work in patients.”
If it does, Shapiro’s discovery would work in conjunction with—not supplant—the current AIDS cocktails already on the market. While these treatments target the virus once inside a host cell, such as interfering with its reverse transcriptase, an enzyme that enables the virus to use the host cell’s machinery to replicate and spread throughout the body, an AAT-like drug would prevent the virus from entering and infecting cells.
“We are targeting the host. We’re basically shielding the virus from the body,” he explains.
A future AAT drug could benefit specific AIDS populations. First, it could reduce the viral loads of chronically infected patients, allowing them to live longer and healthier; second, prevent mother to fetus infection; third, act as a post-exposure prophylactic—for example, following accidental needle sticks—and finally, treat de noveau infections and those resistant to current therapies.
As for possible side effects, Shapiro admits, “I don’t know, but I assume there will be.”
With these caveats in mind, he is proceeding full steam ahead. “In every case [of cultured cells in the lab] we could obtain 90-95% reduction in the HIV [infection]. We knew something was happening.”
When asked whether his philosophy background from Tufts University ever comes in handy as a physician and researcher, Dr. Shapiro, who trained at the University of Massachusetts-Worcester, responds with a smile, “Sure,” as if the secret connections are too strange to explain in public. “Let’s just say sometimes it helps to see things in a different way.”
This unusual perspective may deserve the credit for the discovery of AAT’s HIV inhibiting qualities. According to Shapiro, AAT is one of the best studied molecules in medicine, perhaps so much so that researchers may overlook it.
AAT is the “mother of all serine protease inhibitors,” he says, explaining the fact that human blood has proteases—essential proteins capable of digesting or eating through tissues in the body—and protease inhibitors—proteins that halt the process. The label “serine” describes these proteins’ crystalline structure.
“You can’t have a digester without an inhibitor. There’s a balance normally” between the two, he says.
As for HIV, which Shapiro deems “masterpieces of engineering, very compact, wastes nothing and uses everything,” the virus has its own viral protease, used to provide entry into host cells.
“HIV uses the [viral] proteases to get into the cell and to get out.”
Once inside, the virus takes over the host cell’s machinery to produce more virus. Dr. Shapiro uses the analogy of a computer virus—completely useless on its own—introduced into a computer system or hard drive. There the virus becomes active and harmful.
HIV, which can replicate “up to 10 billion times a day in a patient . . . gets the body to do it for them. Like a computer virus, it must engage the hard drive.”
Because of this reproduction rate, the virus can mutate, creating strains resistant to treatments that try to block infection from inside the cell. “This is a problem with these drugs.”
With an AAT drug, however, “We’re blocking the interface.” And because AAT never mutates and never changes, this could be “a therapy that is resistant to resistance.”
“The story of how this happened is more like a James Bond plot,” the doctor obviously passionate about his subject admits. And like the fictional secret agent, Dr. Shapiro isn’t at liberty to further elucidate on all of the story’s twists and turns.
Similar to many groundbreaking discoveries—like the cell culture in Alexander Fleming’s lab accidentally contaminated with a fungus leading to the detection of penicillin—it was perhaps Shapiro’s unwillingness to ignore negative lab results and his perpetual desire to seek explanations like a four-year-old asks “why” that propelled him to this juncture, even in the midst of naysayers.
It all started, he recounts, with three distinct HIV puzzles of which many researchers also know. The first is the fact that HIV doesn’t grow in whole blood—blood taken directly from a patient. “It made no sense. Everybody seemed to know it but didn’t care,” states Shapiro who, as the quintessential scientist, decided to find out for himself. He tried to grow HIV in whole blood and failed.
“This is an incredible mystery. I began to think of HIV differently.”
The second roadblock on the map to further medical insight was to determine, then, where HIV does grow in a body. He discovered HIV has an affinity for the lymphatic system and the lymph glands, whose chemical make-up is different than blood.
Finally, Shapiro’s third piece that just wouldn’t fit is the relatively low risk of contracting HIV from a contaminated needle stick—about 1 in 250 to 300.
One substance that exists in low levels in the lymph glands, but high levels in blood, is AAT.
“You put them together,” he declares, “and that builds a consistent case. There’s something in the blood that’s blocking the virus.”
Shapiro then conducted several lab studies using purified AAT from healthy blood as well as an AAT-like synthetic to test his theories. All the data showed identical results that AAT reduces HIV infection almost 90-95%.
“There is no question in our minds that this is [due to AAT].”
Whether this turns into an effective pharmaceutical suitable for humans is another matter. Shapiro is working to clone AAT using rational drug design, which could increase the potential treatment’s specificity and decrease the dosage and possible side effects.
“We don’t have a drug yet,” he says cautiously, and what will happen inside a human body remains to be tested.
“We saw the impact on this immediately. Our lab data are very persuasive. Whether that translates into therapy, I don’t know.”
A scientist to watch for, Dr. Shapiro cryptically hints that “this is just part of a very big story. No one would put this together. It has a lot of explanatory power. It’s a new way of understanding the virus.”
Rich, L. E. (2001, January 26). Cure for AIDS? Just maybe, a CU professor is on to it. Intermountain Jewish News.