Stochastic Simulations Suggest that HIV-1 Survives Close to Its Error Threshold

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. Currently available antiretroviral drugs curtail HIV infection but fail to eradicate the virus. A strategy of intervention radically different from that employed by current drugs has been proposed by the molecular quasispecies theory. The theory predicts that increasing the viral mutation rate beyond a critical value, called the error threshold, would cause a severe loss of genetic information, potentially leading to viral clearance. Several chemical mutagens are now being developed that can increase the mutation rate of HIV-1. Their success depends on reliable estimates of the error threshold of HIV-1, which are currently lacking. The quasispecies theory cannot be applied directly to HIV-1: the theory considers an infinitely large population of asexually reproducing haploid individuals, whereas HIV-1 is diploid, undergoes recombination, and is estimated to have a small effective population size in vivo. We employed detailed stochastic simulations that overcome the limitations of the quasispecies theory and accurately mimic HIV-1 evolution in vivo. With these simulations, we estimated the error threshold of HIV-1 to be ~2–6-fold higher than its natural mutation rate, suggesting that HIV-1 survives close to its error threshold and may be readily susceptible to mutagenic drugs.