Biophysical Society Thematic Meeting - November 16-20, 2015

Biophysics in the Understanding, Diagnosis, and Treatment of Infectious Diseases Poster Abstracts

17-POS Board 17 Survival of the Weakest: Less Fit Virus Stabilized in the Face of Drug during Robust HIV Infection Laurelle Jackson 1,2 , Andrew Young 3 , Mikael Boulle 1 , Fabio Zanini 4 , Richard Neher 4 , Gil Lustig 1 , Alex Sigal 1,2,5 . 1 KwaZulu-Natal Research Institute for TB and HIV, Durban, KwaZulu-Natal, South Africa, 2 University of KwaZulu-Natal, Durban, South Africa, 3 Yale Medical School, New Haven, CT, USA, 4 Max Planck Institute for Developmental Biology, Tübingen, Germany, 5 Max Planck Institute for Infection Biology, Berlin, Germany. Current models of drug resistance evolution contend that mutant virus with a higher than wild type fitness will dominate the viral population in the presence of the drug. Counter to this expectation; clinically observed frequencies of highly resistant mutants do not reach 100% of the viral population within the patient. To understand this and examine whether it is dependent on heterogeneity in infection environments, we evolved resistance to efavirenz (EFV), a first line therapy drug, under two different infection conditions: when infection was robust (infected cells consist of 20% of the total cells) and low (infected cells 2% of the total). Counter-intuitively, in robust infection the addition of the drug resulted in delayed evolution of drug resistance and a lower steady-state fraction of mutant virus. This was evident in the mutant virus replication ratio, which decreased as the proportion of mutant in the population increased, until it reached the wild type replication ratio. In contrast, addition of the drug under low infection conditions led to rapid selection of a drug resistant mutant which plateaued at a higher mutant to wild type ratio. To understand the mechanism behind the decrease in mutant fitness, we investigated cell death in robust infection in the face of EFV. We observed that while the proportion of infected cells decreased monotonically in low infection, robust infection showed a peak in the proportion of infected cells at 20nM EFV. EFV increased the number of live infected cells by reducing HIV mediated cell death. The drug resistant mutant lost this protective effect. This implies that in environments where HIV infection is robust (lymph nodes) some drug may be beneficial for the virus and evolution of highly resistant variants will be attenuated.

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