HIV needs errors to survive, but what happens when too many errors are in the mix?
by Chael Needle

Take HIV’s already high rate of mutation and accelerate it until the viral population collapses.

That’s the theory behind a new class of antiviral therapeutics based on viral decay acceleration (VDA), a mechanism developed by biotech Koronis Pharmaceuticals.

VDA builds on Nobel Laureate Manfred Eigen’s concept of a “quasispecies.” A “quasispecies” is a population of constantly evolving virus whose survivability depends on its genomic replication error rate. For example, the HIV population needs to adapt to an environment that is constantly changing due to immune-system, drug, or other pressures. It survives and adapts only because it can mutate and diversify; it mutates and diversifies only because of errors in replication. But it has to be the right amount of errors. Too many errors—“error catastrophe”—and the virus population is subject to collapse, and possibly extinction.

Drs. Larry Loeb and Jim Mullins of the University of Washington and John Essigmann of the Massachusetts Institute of Technology, Koronis’s scientific founders, have applied this concept to RNA-based viruses such as HCV and HIV.

KP1461, an oral prodrug of KP1212, which has shown activity against HIV, and many drug-resistant-conferring mutations, in cell cultures, uses VDA to push on the highly error-prone reverse transcriptase of HIV. Instead of blocking reverse transcriptase so that it can’t do its job in the replication process, as some of the current drugs do, KP1461 is designed to insert itself into a growing DNA strand during the replication process. Replication moves forward, but now with errors that are no good to HIV.

Jim Mullins, PhD, professor of microbiology and medicine at the University of Washington, says that “HIV, like other RNA viruses, exists near the point of extinction. You have a balance between ability to adapt to a changing environment, which requires a lot of mutations, and survivability.

“Because HIV mutates at such a high rate it can achieve quite a bit of variability and can explore many opportunities to escape from immune-system or drug pressures. At the same time, the extremely high recombination rate of HIV, and the fact that HIV exists as this diverse population, allow HIV to not only identify the escape components [read, mutations] but also to recombine them with features of the virus that allow continuing strong replication.
“The fact that HIV exists as this flexible, interchanging, slot machine kind of virus population is beneficial to its survival.”

Errors in genomic replication, however, may be the Achilles’ heel of the virus. “HIV exists near this point of error catastrophe and it looks like you only need about a one-and-a-half or two-fold increase in the number of mutations in the population to extinguish the virus,” says Dr. Mullins about a characteristic well studied in other RNA viral systems. “In our study it’s been somewhere between a 1.5 and 1.8-fold difference. So fifty to eighty percent more mutations—very little increase in mutational burden—will knock out the replicating population.”

Through incorporation into HIV’s genomic replication and its resulting inducement of errors, KP1461 may show the ability to disrupt this “very fine balance.” Disruption needs this kind of push. Says Dr. Mullins: “For survival to occur [the virus] has to live on the other side of that brink [of error catastrophe]. HIV doesn’t burn itself out in people. Once it’s going, it’s going. There’s really no evidence that HIV by itself will fall over the edge and extinguish itself.”

Dr. Mullins recently presented clinical trial data that demonstrated KP1461’s ability to increase HIV mutations in people. No drug-associated toxicity was noted, in this or any other trial of KP1461. Though the ultimate goal is collapse, Dr. Mullins reminded that no one expected to see that happen, and it did not: “There was just not enough time and in hindsight perhaps not enough available drug.”

Additional challenges lie ahead. For example, researchers at Koronis would like to explore VDA technology’s ability to deplete functional viral reservoirs. Next up, however, is a plan to conduct a longer trial, one with increased bioavailability, and to evaluate what the best patient population for this investigational drug might be.

Dr. Mullins is currently intrigued by KP1461 as an adjuvant to a failing antiretroviral regimen in treatment-experienced patients. “Maintaining people on therapy has some benefit despite the fact that there’s been virologic breakthrough,” he reminds. “The viruses that are replicating in those individuals are by and large expected to be less fit, and therefore in my mind theoretically closer to the point of error catastrophe. Increasing the mutational burden on people who have virus in that state I think would be likely to show a more immediate benefit.”

Koronis hopes to launch studies based on both adjuvant and monotherapeutic approaches. “I hope this mechanism gets an opportunity to get explored thoroughly. Honestly the big money is in the already proven mechanisms but I think it’s shortsighted to not be developing a pipeline based on new ways of attacking the virus.”

Chael Needle wrote about probiotics in the fight against HIV in the October issue.

November 2010