Recombination Enhances HIV-1 Envelope Diversity by Facilitating the Survival of Latent Genomic Fragments in the Plasma Virus Population

HIV-1 is subject to immune pressure exerted by the host, giving variants that escape the immune response an advantage. Virus released from activated latent cells competes against variants that have continually evolved and adapted to host immune pressure. Nevertheless, there is increasing evidence that virus displaying a signal of latency survives in patient plasma despite having reduced fitness due to long-term immune memory. We investigated the survival of virus with latent envelope genomic fragments by simulating within-host HIV-1 sequence evolution and the cycling of viral lineages in and out of the latent reservoir. Our model incorporates a detailed mutation process including nucleotide substitution, recombination, latent reservoir dynamics, diversifying selection pressure driven by the immune response, and purifying selection pressure asserted by deleterious mutations. We evaluated the ability of our model to capture sequence evolution in vivo by comparing our simulated sequences to HIV-1 envelope sequence data from 16 HIV-infected untreated patients. Empirical sequence divergence and diversity measures were qualitatively and quantitatively similar to those of our simulated HIV-1 populations, suggesting that our model invokes realistic trends of HIV-1 genetic evolution. Moreover, reconstructed phylogenies of simulated and patient HIV-1 populations showed similar topological structures. Our simulation results suggest that recombination is a key mechanism facilitating the persistence of virus with latent envelope genomic fragments in the productively infected cell population. Recombination increased the survival probability of latent virus forms approximately 13-fold. Prevalence of virus with latent fragments in productively infected cells was observed in only 2% of simulations when we ignored recombination, while the proportion increased to 27% of simulations when we allowed recombination. We also found that the selection pressures exerted by different fitness landscapes influenced the shape of phylogenies, diversity trends, and survival of virus with latent genomic fragments. Our model predicts that the persistence of latent genomic fragments from multiple different ancestral origins increases sequence diversity in plasma for reasonable fitness landscapes.

HIV-1会受到宿主施加的免疫压力，这使得逃避免疫应答的变异株获得生存优势。从激活的潜伏细胞中释放的病毒，会与那些持续进化并适应宿主免疫压力的变异株展开竞争。尽管如此，越来越多的证据表明，尽管因长期免疫记忆而出现适合度（fitness）下降，但带有潜伏特征的病毒仍可在患者血浆中存活。我们通过模拟宿主内HIV-1序列进化，以及病毒谱系在潜伏库（latent reservoir）内外的循环，探究了带有潜伏包膜基因组片段的病毒的存活情况。本模型整合了细致的突变过程，包括核苷酸替换、重组、潜伏库动力学、由免疫应答驱动的歧化选择压力（diversifying selection pressure），以及由有害突变引发的纯化选择压力（purifying selection pressure）。我们将模拟序列与16名未经治疗的HIV感染患者的HIV-1包膜序列数据进行比对，以此评估模型捕捉体内序列进化的能力。实证序列的歧异度与多样性指标在定性与定量层面均与我们模拟的HIV-1种群结果相似，这表明本模型还原了HIV-1遗传进化的真实趋势。此外，模拟种群与患者HIV-1种群的重建系统发育树展现出相似的拓扑结构。本模拟结果表明，重组是促使带有潜伏包膜基因组片段的病毒在产毒感染细胞群体（productively infected cell population）中持续存在的关键机制。重组使潜伏病毒形式的存活概率提升了约13倍。当忽略重组时，仅在2%的模拟场景中可观察到带有潜伏片段的病毒在产毒感染细胞中的流行率；而当允许重组发生时，这一比例提升至27%。我们还发现，不同适合度景观（fitness landscapes）施加的选择压力，会影响系统发育的形态、多样性变化趋势以及带有潜伏基因组片段的病毒的存活情况。本模型预测，对于合理的适合度景观而言，来自多种不同祖先起源的潜伏基因组片段的持续存在，会提升血浆中的序列多样性。