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, , however, is not known. Application of the quasispecies theory to determine 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 . 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 to be substitutions/site/replication, ∼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, 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 may serve as a quantitative guideline for the use of mutagenic drugs against HIV-1.
Highlights
The high mutation rate of HIV-1 coupled with its massive turnover rate in vivo results in the continuous generation of mutant viral genomes that are resistant to administered drugs and can evade host immune responses [1,2]
When the mutation rate is increased beyond a critical value, called the error threshold, the quasispecies delocalizes in sequence space, inducing a severe loss of genetic information–a phenomenon termed error catastrophe–and compromising the viability of the viral population
A strategy of intervention radically different from that employed by current drugs has been proposed by the molecular quasispecies theory
Summary
The high mutation rate of HIV-1 coupled with its massive turnover rate in vivo results in the continuous generation of mutant viral genomes that are resistant to administered drugs and can evade host immune responses [1,2]. The theory predicts that a collection of closely related but distinct genomes, called the quasispecies, exists in an infected individual when the viral mutation rate is small. When the mutation rate is increased beyond a critical value, called the error threshold, the quasispecies delocalizes in sequence space, inducing a severe loss of genetic information–a phenomenon termed error catastrophe–and compromising the viability of the viral population. 4-fold increase in the mutation rate induced a dramatic 70% loss of poliovirus infectivity in vitro [9]. Chemical mutagens have been employed successfully to enhance the mutation rates of a host of other viruses [10,11,12,13] including HIV-1 [14,15,16,17]. An HIV-1 mutagen is currently under clinical trials [18]
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