PMID- 19014593
OWN - NLM
STAT- MEDLINE
DCOM- 20090128
LR  - 20211020
IS  - 1742-4682 (Electronic)
IS  - 1742-4682 (Linking)
VI  - 5
DP  - 2008 Nov 14
TI  - Transient antiretroviral therapy selecting for common HIV-1 mutations 
      substantially accelerates the appearance of rare mutations.
PG  - 25
LID - 10.1186/1742-4682-5-25 [doi]
AB  - BACKGROUND: Highly selective antiretroviral (ARV) regimens such as single dose 
      nevirapine (NVP) used for prevention of mother to child transmission (PMTCT) in 
      resource-limited settings produce transient increases in otherwise marginal 
      subpopulations of cells infected by mutant genomes. The longer term implications 
      for accumulation of further resistance mutations are not fully understood. 
      METHODS: We develop a new strain-differentiated hybrid deterministic-stochastic 
      population dynamic type model of healthy and infected cells. We explore how the 
      transient increase in a population of cells transcribed with a common mutation 
      (modelled deterministically), which occurs in response to a short course of 
      monotherapy, has an impact on the risk of appearance of rarer, higher-order, 
      therapy-defeating mutations (modelled stochastically). RESULTS: Scenarios with a 
      transient of a magnitude and duration such as is known to occur under NVP 
      monotherapy exhibit significantly accelerated viral evolution compared to 
      no-treatment scenarios. We identify a possibly important new biological 
      timescale; namely, the duration of persistence, after a seminal mutation, of a 
      sub-population of cells bearing the new mutant gene, and we show how increased 
      persistence leads to an increased probability that a rare mutant will be present 
      at the moment at which a new treatment regimen is initiated. CONCLUSION: Even 
      transient increases in subpopulations of common mutants are associated with 
      accelerated appearance of further rarer mutations. Experimental data on the 
      persistence of small subpopulations of rare mutants, in unfavourable 
      environments, should be sought, as this affects the risk of subverting later 
      regimens.
FAU - Shiri, Tinevimbo
AU  - Shiri T
AD  - School of Computational and Applied Mathematics, University of the Witwatersrand, 
      Private Bag 3, Johannesburg, South Africa. tshiri@cam.wits.ac.za
FAU - Welte, Alex
AU  - Welte A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20081114
PL  - England
TA  - Theor Biol Med Model
JT  - Theoretical biology & medical modelling
JID - 101224383
RN  - 0 (Antiviral Agents)
RN  - 99DK7FVK1H (Nevirapine)
SB  - IM
MH  - Antiviral Agents/pharmacology
MH  - Female
MH  - Genome
MH  - HIV Infections/*drug therapy/transmission
MH  - HIV-1/*genetics
MH  - Humans
MH  - Infectious Disease Transmission, Vertical
MH  - Models, Statistical
MH  - *Mutation
MH  - Nevirapine/pharmacology
MH  - Pregnancy
MH  - Pregnancy Complications, Infectious
MH  - Risk
MH  - Stochastic Processes
MH  - Virology/methods
PMC - PMC2605440
EDAT- 2008/11/19 09:00
MHDA- 2009/01/29 09:00
PMCR- 2008/11/14
CRDT- 2008/11/19 09:00
PHST- 2008/07/25 00:00 [received]
PHST- 2008/11/14 00:00 [accepted]
PHST- 2008/11/19 09:00 [pubmed]
PHST- 2009/01/29 09:00 [medline]
PHST- 2008/11/19 09:00 [entrez]
PHST- 2008/11/14 00:00 [pmc-release]
AID - 1742-4682-5-25 [pii]
AID - 10.1186/1742-4682-5-25 [doi]
PST - epublish
SO  - Theor Biol Med Model. 2008 Nov 14;5:25. doi: 10.1186/1742-4682-5-25.