"We were interested in what shifted in the evolutionary dynamics between the 1980s, when patients failed all the time, versus 2015 or 2016, when patients do really well on therapy," said lead author Alison Feder, a graduate student in biology at Stanford who conducted the work in the lab of Stanford biology Professor Dmitri Petrov.
By combing through historical HIV records from the
Stanford HIV Drug Resistance Database, Feder and her colleagues found that two specific mutation patterns could be used as indicators of treatment viability.
In some cases, the virus becomes drug resistant while retaining genetic diversity within a host. A high rate of mutations in the population gives the virus more opportunities to develop multiple simultaneous drug-resistant mutations that spread throughout the viral population within the patient at the same time, thus maintaining high amounts of diversity. This is called a "soft sweep."
"Hard sweeps," on the other hand, occur when a virus develops only a single successful resistant mutation. When this one mutation spreads throughout the body, the virus becomes genetically homogeneous. In these populations, it's rare that the single mutation is for drug resistance.
"Our guess was that in the early days of HIV treatment when resistance failure was really common, drug resistance evolution must have been driven by soft sweeps," said Feder.
This knowledge will not necessarily improve modern HIV treatments – they perform well already – but the discovery of how viruses evolve in response to different treatments has a surprising payoff for drug development for other diseases: It allows scientists to determine the effectiveness of a drug from
how it fails instead of
how often it fails.
Normally, testing drugs requires a full clinical trial based on detailed information about the patients. A clinical trial usually measures the effectiveness of a drug by comparing the number of participants who are doing fine to those who have developed resistance after a certain span of time.
Based on the new HIV finding, researchers could potentially focus on the virus population within the patients who have developed resistance. If the treatment failed via hard sweeps, it might indicate the patient simply developed an unlucky mutation and thus the drug has broader promise. If, however, a soft sweep were responsible for the failure, the researcher would know that this treatment could be likely to fail in most patients, and resources should be devoted to other, more promising drugs.