Department of Chemical Engineering, Indian Institute of Science, Bangalore, India.
PLoS Comput Biol. 2012;8(9):e1002684. doi: 10.1371/journal.pcbi.1002684. Epub 2012 Sep 13.
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, μ c, however, is not known. Application of the quasispecies theory to determine μ 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 μ 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 μ c to be 7 x 10(-5)-1 x 10(-4) 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, μ 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 μ c may serve as a quantitative guideline for the use of mutagenic drugs against HIV-1.
利用诱变药物使 HIV-1 越过其错误阈值，这是一种新的干预策略，正如准种理论所表明的那样，与当前的策略相比，这种策略不太可能因病毒突变引起的耐药性而失败。然而，HIV-1 的错误阈值 μc 尚不清楚。应用准种理论来确定 μc 存在很大的挑战：虽然准种理论考虑了无限大的单倍体个体的无性繁殖，但 HIV-1 是二倍体，会发生重组，并且在体内估计有效种群规模较小。我们进行了基于种群遗传学的 HIV-1 体内进化的随机模拟，并估计了 HIV-1 准种和 μc 的结构。我们发现，在较小的突变率下，准种主要由突变较少的基因组主导。随着突变率的增加，会发生急剧的错误灾难，准种在序列空间中变得非本地化。使用定量捕获 HIV-1 患者病毒多样化数据的参数值，我们估计 μc 为 7 x 10(-5)-1 x 10(-4)个取代/位/复制，约为 HIV-1 自然突变率的 2-6 倍，表明 HIV-1 接近其错误阈值，并且可能容易受到诱变药物的影响。后一个估计值与 HIV-1 的体内有效种群规模弱相关。在大的种群规模和没有重组的情况下，我们的模拟收敛到准种理论，弥合了准种理论和基于种群遗传学的方法之间描述 HIV-1 进化的差距。此外，μc 随着重组率的增加而增加，使 HIV-1 不易发生错误灾难，从而阐明了重组对 HIV-1 的额外好处。我们对 μc 的估计可以作为针对 HIV-1 使用诱变药物的定量指南。
