73 / 101
Biophysics in the Understanding, Diagnosis, and Treatment of Infectious Diseases Poster Abstracts
68
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.