GRA Eminent Scholar's discovery leads to licensing agreement

GRA Eminent Scholar Vasu Nair believes he has found a weak link in the process that allows the human immunodeficiency virus (HIV) to replicate and cause AIDS. By exploiting this weakness, he believes he can stop viral reproduction and keep people infected with HIV from developing AIDS.

His drug discovery has won the interest of a Georgia biopharmaceutical company, Inhibitex, which in September 2007 entered an exclusive licensing agreement with the University of Georgia Research Foundation for the rights to the drug. Inhibitex began IND-enabling studies in 2008. The company also is sponsoring three years of additional research on the drug at UGA.

Dr. Nair has carefully studied the chain of events that allows HIV to replicate. Based on more than 15 years of research, he developed a drug that targets an enzyme that sparks a biological chain reaction causing the virus to replicate.

The enzyme is called HIV integrase, and it enables HIV to incorporate its DNA into human DNA. Once the virus has accomplished this, the host cells become like virus factories, producing more viral cells every day. If the replication process can be short-circuited, a person infected with HIV might never develop AIDS.

“Until replication reaches the full-blown state,” Dr. Nair says, “many people show no ill effects at all.”

When HIV enters the body, it is not yet capable of causing AIDS. “The number of viral particles that you start out with in the system is relatively low — they’re not able to significantly impact the immune system,” says Dr. Nair.

But by the time a person reaches even the early stages of AIDS, the number of viral particles produced each day may be in the many hundreds of millions to more than a billion, incapacitating the immune system, allowing infections to run rampant, and eventually killing the host.

The period of time from initial infection to full-blown AIDS may be as short as a few years or as long as a decade or more. Dr. Nair says this time gives scientists and doctors “windows in which to act.”

“If we can stop the virus from getting its DNA incorporated into the host’s DNA, then it can’t replicate,” Dr. Nair explains. “This enzyme presents a particularly attractive target because we humans don’t need to integrate our DNA with a foreign organism’s genetic material.” As a result, he says, any treatments that disable or even destroy HIV integrase are less likely to harm the patient in the process.

Early in their research, Dr. Nair and his team realized that HIV integrase recognized certain chemical components of DNA that made it “want” to incorporate into human DNA.

“The strongest of these attractions was to a pyrimidine, a basic component of DNA,” Dr. Nair says. “So we built our inhibitor around a pyrimidine scaffold. The pyrimidine functions like a fishing lure for HIV integrase.”

The enzyme recognizes the pyrimidine scaffold and latches onto the inhibitor, which in effect hooks HIV integrase so that it cannot escape and bind to the host DNA. Eventually the enzyme/inhibitor compound is eliminated by natural bodily processes.

Shutting viral replication down to a trickle could dramatically increase the treatment options available to patients. Today, patients face costly and painful injections, constant pill administration and occasionally near-fatal side effects.

Not so if Dr. Nair’s work continues in its current vein. “Like diabetics who measure blood-sugar levels and take insulin on a regular basis, a person infected with HIV would be able to monitor viral counts and medicate accordingly,” Dr. Nair says.

Moreover, this basic approach need not be limited to HIV.

“Maybe the most interesting thing about our discovery is its ramifications for other viruses,” Dr. Nair says. Because HIV is a retrovirus — meaning that it injects its genetic material into a host cell, then takes advantage of the infected cells’ machinery to manufacture more viral invaders — targeting this integrase may work to halt the progress of other retroviruses, such as the virus that causes feline leukemia and several other kinds of tumor-causing, retroviral infections.

“The isolation of this integrase and the construction of an effective inhibitor for it could impact treatments of many viral infections,” Dr. Nair says. “That’s because the basic design concepts from our discovery can be modified and applied to other retroviruses and other DNA viruses.”

Dr. Nair acknowledges that drug targeting and discovery is a complicated process. Side effects, for example, are a major concern when focusing on new targets for drugs. Before clinical trials — which test the safety and effectiveness of a treatment — can begin, extensive toxicity studies in pre-clinical trials are required.

“It does me no good to invent a ‘cure-all’ that kills the patient in the process,” he says. “But the good news about HIV integrase is that it has no parallel in the human body, so this may lower the likelihood of harmful side effects arising from a drug targeting this enzyme.”

By contrast, AZT, a common treatment for HIV/AIDS, targets an enzyme called reverse transcriptase that is also involved in viral DNA replication. But, because humans also replicate their DNA, the drug interferes with this replication as well as the viral process, resulting in side effects such as anemia, nausea, severe muscle weakness and extreme fatigue.

“After some period of time working with reverse-transcriptase inhibitors, we decided to look elsewhere and try to disable the enzyme that actually gets the genetic information into the host’s genetic code,” Dr. Nair says.