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By David Warmflash

David WarmflashTogether with the long-term battle against human immunodeficiency virus (HIV), the various strains of hepatitis virus, and other viral diseases that run rampant in our population, the current outbreak of Ebola in West Africa highlights viral disease as one of the major challenges that beckon to 21st century biomedicine. Along with cancers (some of which are known to have viral etiologies), pathogenic viruses generally are more difficult to combat with pharmacologic methods compared with definitive organisms, such as bacteria and protozoan parasites. But like bacterial disease, parasites, fungal organisms, and cancer, the overall strategy with viruses is to find vulnerabilities and attack those with agents that don’t exert similar effects against healthy, human cells.

Therapeutic tactics include a number of therapies that seek to disrupt the spread of the virus. Examples include blocking receptors that allow a virus to bind or enter host cells, inhibition of viral uncoating, inhibition of enzymes that integrate the viral genome into the DNA of host cells, inhibition of DNA replication, inhibition of DNA transcription, inhibition of the translation and processing of viral proteins, blocking assembly of the viral coat, and inhibition of reverse transcriptase.

But viruses can evade drug therapy. For instance, while the current approach to HIV treatment using multiple tactics to attack the virus often allows patients to achieve remission, the virus is still latent in T cells and reactivates when the treatment stops. Some viruses also can develop drug resistance. Genetic mutation provides a source of potential new characteristics, including drug resistance, and newly mutated genes are sieved in a selection process.

There’s a limit to how much mutation can be tolerated. Mutating slowly, it’s difficult to generate beneficial mutations. Nevertheless, at a slow rate of mutation, once in a while, something beneficial arises that makes the organism (or virus) stronger than its parents. If the process is accelerated, it’s still possible for new beneficial traits to arise, but only up to a certain point. If mutation occurs beyond a certain rate, they cannot survive, although the mutation rate itself is subject to evolution based on the environmental pressures. Utilizing this phenomenon as a kind of viral Achilles heal, a new study has examined hypermutation as a potential treatment. By stimulating an unusually high rate of mutation as the viral genetic material is replicated in the host cells, the virus can be made to mutate itself to extinction.

DNA strands with emphasis on bonds between nucleotides.

DNA strands with emphasis on bonds between nucleotides.

It works due to the chemical phenomenon of tautomerization, in which compounds switch around between different isomers. The experimental drug, KP1212, tautomerizes between thymine and cytosine, two of the nitrogenous bases used in DNA. In normal base pairing, thymine pairs with adenine of the opposite DNA strand, while cytosine pairs with guanine. Thus, KP1212 causes incorrect base pairing, leading to numerous mutations in DNA replication and does the same in RNA replication (which uses uracil in place of thymine, but is confused similarly by the drug).

KP1212 does not affect healthy, uninfected human cells, because it’s specific to the viral DNA replicase and RNA replicase enzymes. It is thought that adding the hypermutation strategy to the current anti-HIV cocktail (which uses protease inhibitors, reverse transcriptase inhibitors and other tactics) can facilitate destruction of the viral sequences that survive latent in the patient’s cells.

The idea is so promising that the therapeutic strategy need not be limited to HIV. It should also be useful against various other viruses. And while the literature does not show any testing of KP1212 against Ebola, the hypermutation has been discussed as a potential treatment against other RNA viruses, such as yellow fever, dengue fever, and also possibly against cancer.

David Warmflash, M.D., is an astrobiologist, science writer, and physician. He is principal investigator on a Planetary Society-sponsored investigation of the effects of the space environment on organisms.