Why Our Drugs are No Match for HIV

I recently received the following question regarding anti-HIV therapy:

“What do you think is the solution for these multiple drug resistant strains of HIV and other viruses? There's got to be a limit to the viral genome, to how many resistant mechanisms a virus can store, right? Seems to me the persistence of human researchers has got to wear these viruses down eventually since evolution only gave them so many tools.”

If there were ever a professional evolver, HIV would be it. I took the following statistics from Principles of Virology, which has a great background discussion of HIV, in case anyone is interested in learning more.

-At least 10¹⁰ virions are released into the blood per day

-Because of the high mutation rate of HIV, on average, every possible mutation at every position in the genome is predicted to occur numerous times each day

-Based on the high rates of mutation and virus propagation, it has been estimated that the genetic diversity of HIV produced in a single infected individual can be greater than the worldwide diversity of influenza virus during an epidemic

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The idea that there is a limit to the HIV genome may seem sound, but in thinking about viral evolution, we cannot simply apply our framework of eukaryote evolution. For instance, given the rate of human reproduction, it would make no sense for us to have high mutation rates, because eventually we’d die off (as a general rule, mutations overwhelmingly cause decreases rather than increases in viability). However, the case is different for HIV. Although MANY of the viruses that result from mutation events are incapable of infection, the magnitude of viruses that are produced, and the small chance that a mutant will be more infectious given the conditions at the time, far outweighs the energy required to make all those viruses. This brings up another point. For humans, there is a significant energy output to create another human, so it becomes important to have a high degree of genomic fidelity and protect against deleterious mutations. In contrast, the virus has no reason to “care” about the energy expelled on inviable mutants over the course of replication and evolution, because ultimately, it’s the human host that expends the energy for these processes anyway. For the virus, it’s a win-win situation. This becomes especially true when the virus is not just attempting to evade the host’s natural immune defenses but also has to resist the drugs the host may take.

Currently, the best therapeutic strategy is to defend against viral proliferation with a suite of drugs. These drugs are administered simultaneously, and each targets a different facet of the viral infectious cycle. The idea behind this strategy is probabilistic: although a mutant virus may arise that is resistant to one of the drugs being administered, it will be less likely that that same virus will survive in the presence of two drugs, and less likely still that it will survive under the pressure of three drugs, etc. Of course, implicating this kind of treatment is not a trivial undertaking—it requires the patient to take as many as fifty pills each day, complete with devastating side effects. And yet, given the degree of viral replication and mutation, preliminary results from these treatments have been far from promising. One critical issue is that the virus infects and replicates in the host for as long as a decade before the infection becomes apparent. If treatment is not begun until symptoms arise, the individual already harbors a viral population of enormous genetic diversity. In these cases, it is theoretically impossible to combat every viral variant. In fact, it's likely that such a patient will harbor an HIV mutant resistant to any drug or combination of drugs that could ever be tested.

Case in point: viral mutants resistant to AZT appeared almost immediately after the drug was approved.

The quest against HIV looks grim, although HIV researchers are constantly uncovering new information that can be applied to novel treatments. It’s possible that an effective HIV vaccine or drug will result one day, but I strongly suspect that it will not be a matter of wearing down the evolution of the virus. Evolution did not give HIV a finite number of “tools” to use to evade human defense. Rather, evolution is continuously conferring on HIV the mutations necessary to resist the attacks of researchers and health care professionals alike. As is used so often to describe virus:host interactions, it is truly an arms race, and HIV is a massive and unpredictable army.