McKinley Scott A, Chen Alex, Shi Feng, Wang Simi, Mucha Peter J, Forest M Gregory, Lai Samuel K
Mathematics Department, University of Florida, Gainesville, Florida, United States of America.
Departments of Mathematics and Applied Physical Science, University of North Carolina - Chapel Hill, Chapel Hill, North Carolina, United States of America; Statistical and Applied Mathematical Sciences Institute, Research Triangle Park, North Carolina, United States of America.
PLoS One. 2014 Jun 26;9(6):e100598. doi: 10.1371/journal.pone.0100598. eCollection 2014.
Eliciting broadly neutralizing antibodies (bnAb) in cervicovaginal mucus (CVM) represents a promising "first line of defense" strategy to reduce vaginal HIV transmission. However, it remains unclear what levels of bnAb must be present in CVM to effectively reduce infection. We approached this complex question by modeling the dynamic tally of bnAb coverage on HIV. This analysis introduces a critical, timescale-dependent competition: to protect, bnAb must accumulate at sufficient stoichiometry to neutralize HIV faster than virions penetrate CVM and reach target cells. We developed a model that incorporates concentrations and diffusivities of HIV and bnAb in semen and CVM, kinetic rates for binding (kon) and unbinding (koff) of select bnAb, and physiologically relevant thicknesses of CVM and semen layers. Comprehensive model simulations lead to robust conclusions about neutralization kinetics in CVM. First, due to the limited time virions in semen need to penetrate CVM, substantially greater bnAb concentrations than in vitro estimates must be present in CVM to neutralize HIV. Second, the model predicts that bnAb with more rapid kon, almost independent of koff, should offer greater neutralization potency in vivo. These findings suggest the fastest arriving virions at target cells present the greatest likelihood of infection. It also implies the marked improvements in in vitro neutralization potency of many recently discovered bnAb may not translate to comparable reduction in the bnAb dose needed to confer protection against initial vaginal infections. Our modeling framework offers a valuable tool to gaining quantitative insights into the dynamics of mucosal immunity against HIV and other infectious diseases.
在宫颈阴道黏液（CVM）中诱导产生广泛中和抗体（bnAb）是一种很有前景的“第一道防线”策略，可减少阴道HIV传播。然而，目前尚不清楚CVM中必须存在何种水平的bnAb才能有效降低感染风险。我们通过对HIV上bnAb覆盖的动态计数进行建模来解决这个复杂问题。该分析引入了一个关键的、与时间尺度相关的竞争：为了起到保护作用，bnAb必须以足够的化学计量积累，以便比病毒粒子穿透CVM并到达靶细胞的速度更快地中和HIV。我们开发了一个模型，该模型纳入了HIV和bnAb在精液和CVM中的浓度及扩散系数、选定bnAb的结合（kon）和解离（koff）动力学速率，以及CVM和精液层的生理相关厚度。全面的模型模拟得出了关于CVM中中和动力学的有力结论。首先，由于精液中的病毒粒子穿透CVM所需的时间有限，CVM中必须存在比体外估计值高得多的bnAb浓度才能中和HIV。其次，该模型预测，kon更快的bnAb，几乎与koff无关，在体内应具有更强的中和效力。这些发现表明，最早到达靶细胞的病毒粒子感染的可能性最大。这也意味着，许多最近发现的bnAb在体外中和效力上的显著提高，可能无法转化为在预防初次阴道感染所需的bnAb剂量上的可比降低。我们的建模框架为深入了解针对HIV和其他传染病的黏膜免疫动力学提供了一个有价值的工具。
