by John S. James Summary: KP-1461, an experimental HIV drug already in a phase II trial, works so differently from other antiretrovirals that at first glance it looked like science fiction, and we found it hard to take seriously as a current possibility today. In fact this drug is highly credible, and based on elegant science that goes back at least 25 years. KP-1461 is the only antiretroviral in human use or testing that can eradicate HIV from laboratory cell cultures. No one knows how it will work in people — but we might know by the second quarter of 2008, when the current phase II trial could be complete. AIDS Treatment News interviewed Dr. Stephen Becker, a leading AIDS physician and researcher who is vice president of clinical development at Koronis Pharmaceuticals, in Seattle, Washington. —————————————- Summary: KP-1461, an experimental HIV drug already in a phase II trial, works so differently from other antiretrovirals that at first glance it looked like science fiction, and we found it hard to take seriously as a current possibility today. In fact this drug is highly credible, and based on elegant science that goes back at least 25 years. KP-1461 is the only antiretroviral in human use or testing that can eradicate HIV from laboratory cell cultures. No one knows how it will work in people — but we might know by the second quarter of 2008, when the current phase II trial could be complete. AIDS Treatment News interviewed Dr. Stephen Becker, a leading AIDS physician and researcher who is vice president of clinical development at Koronis Pharmaceuticals, in Seattle, Washington. Background: The scientific story began when Mansfeld Eigen (who had already won a Nobel Prize in chemistry for other work) applied his chemistry and mathematics background to problems in biology, and with Peter Schuster and others developed the concept of quasispecies. Standard Darwinian evolution predicts that the fittest strain of an organism, the one that reproduces fastest in a given environment, will displace the other strains there. But a virus like HIV is different; it is always mutating, and can mutate back and forth between different strains. The result is that HIV, in a patient with advanced infection or AIDS, exists as millions of related strains within the same patient (usually only one was transmitted, and then it evolved within that individual into countless slightly different variants). This makes HIV hard to treat, because some members of the quasispecies probably already have resistance mutations to a new drug even by chance alone, and these resistant viruses are ready to be selected and become much more prevalent when the drug is started. The conventional approach to this problem is to use combinations of different drugs, hoping to suppress HIV to such a low level that little mutation and evolution can take place. This may suppress the virus for years, but has never succeeded in eradicating it, so patients usually have to stay on treatment for life. Quasispecies follow different rules than Darwinian evolution. For example, it is possible at least in theory for the strain that reproduces fastest to be replaced entirely by strains that individually reproduce more slowly, but are more fit as a quasispecies. Eigen and Schuster also wrote a well-known book, The Hypercycle: A Principle of Natural Self-Organization, published in 1979 on quasispecies and related concepts. A way to attack a quasispecies as a whole is to increase the already-high mutation rate, leading to an “error catastrophe” and collapse of the population. This approach was used to design the drug now in a phase II trial, KP-1461. KP-1461 is a nucleoside analog, like AZT, 3TC, and the others; once inside the cell it is chemically modified (triphosphorylated) into its active form (called KP-1212), which can replace one of the four bases used to make DNA. (The four bases are adenosine, cytodine, thymidine, and guanosine — some say that the initials ‘ACTG’ for the government AIDS clinical-trials network were not just coincidence.) In DNA the bases are paired, forming the famous double helix; cytidine always pairs with guanosine, and thymidine always pairs with adenosine. KP-1212 can replace cytidine when the viral enzyme reverse transcriptase is building a new copy of HIV, and pair normally with guanosine. It does not terminate the DNA chain. But KP-1212 was chemically designed to be a flexible molecule, such that it can also look like thymidine and then pair with adenosine. This introduces an error that then is locked into the viral DNA. These errors happen at random, anywhere in the virus; and when they do not kill the virus outright, they accumulate over generations in the DNA of the viral population. The result is eventually an error catastrophe that can wipe out the entire quasispecies, at least in laboratory tests. If you then take the drug away, the virus does not come back. And the cells on which the virus grew are still alive — cured of the infection. AZT and the other approved nucleoside analogs terminate the growth of the DNA chain, killing the copy of virus being built. But that copy is easily replaced by other copies that do not have an abnormal error accumulation, so the population as a whole is not damaged. In contrast, KP-1212 continues to add new errors to the population, in addition to the errors that are already there due to the very high normal mutation rate of HIV. For detailed scientific background, see [1]. * * * AIDS Treatment News interviewed Dr. Stephen Becker in mid September 2007. Dr. Becker, who has been well known for years as a leading AIDS clinician and scientist, was hired last year by Koronis Pharmaceuticals, a small company in Seattle, Washington, to design and conduct the clinical trial that could lead to proof of principle of KP-1461. Interview with Dr. Becker AIDS Treatment News: Am I correct in believing that KP-1461 causes lots of mutations of HIV? Dr. Becker: Yes. KP-1461 is a nucleoside analog [a false building block