Tripathi, Kushal and Balagam, Rajesh and Vishnoi, Nisheeth K and Dixit, Narendra M (2012) Stochastic Simulations Suggest that HIV-1 Survives Close to Its Error Threshold. In: PLOS COMPUTATIONAL BIOLOGY, 8 (9).
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Abstract
The use of mutagenic drugs to drive HIV-1 past its error threshold presents a novel intervention strategy, as suggested by the quasispecies theory, that may be less susceptible to failure via viral mutation-induced emergence of drug resistance than current strategies. The error threshold of HIV-1, mu(c), however, is not known. Application of the quasispecies theory to determine mu(c) poses significant challenges: Whereas the quasispecies theory considers the asexual reproduction of an infinitely large population of haploid individuals, HIV-1 is diploid, undergoes recombination, and is estimated to have a small effective population size in vivo. We performed population genetics-based stochastic simulations of the within-host evolution of HIV-1 and estimated the structure of the HIV-1 quasispecies and mu(c). We found that with small mutation rates, the quasispecies was dominated by genomes with few mutations. Upon increasing the mutation rate, a sharp error catastrophe occurred where the quasispecies became delocalized in sequence space. Using parameter values that quantitatively captured data of viral diversification in HIV-1 patients, we estimated mu(c) to be 7 x 10(-5) -1 x 10(-4) substitutions/site/replication, similar to 2-6 fold higher than the natural mutation rate of HIV-1, suggesting that HIV-1 survives close to its error threshold and may be readily susceptible to mutagenic drugs. The latter estimate was weakly dependent on the within-host effective population size of HIV-1. With large population sizes and in the absence of recombination, our simulations converged to the quasispecies theory, bridging the gap between quasispecies theory and population genetics-based approaches to describing HIV-1 evolution. Further, mu(c) increased with the recombination rate, rendering HIV-1 less susceptible to error catastrophe, thus elucidating an added benefit of recombination to HIV-1. Our estimate of mu(c) may serve as a quantitative guideline for the use of mutagenic drugs against HIV-1.
| Item Type: | Journal Article |
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| Publication: | PLOS COMPUTATIONAL BIOLOGY |
| Publisher: | PUBLIC LIBRARY SCIENCE |
| Additional Information: | Copyright for this article belongs to the authors. |
| Department/Centre: | Division of Mechanical Sciences > Chemical Engineering |
| Date Deposited: | 13 Feb 2013 10:36 |
| Last Modified: | 13 Feb 2013 10:36 |
| URI: | http://eprints.iisc.ac.in/id/eprint/45348 |
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