Modeling neutralization kinetics of HIV by broadly neutralizing monoclonal antibodies in genital secretions coating the cervicovaginal mucosa.
Modeling neutralization kinetics of HIV by broadly neutralizing monoclonal antibodies in genital secretions coating the cervicovaginal mucosa.
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DOI：
10.1371/journal.pone.0100598
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Lai SK
中科院分区：
文献类型：
--
作者：
McKinley SA;Chen A;Shi F;Wang S;Mucha PJ;Forest MG;Lai SK
在宫颈阴道粘液(CVM)中诱导广谱中和抗体(BNab)是一种很有前途的减少艾滋病毒经阴道传播的“第一道防线”策略。然而，目前尚不清楚CVM中必须存在什么水平的bNab才能有效地减少感染。我们通过模拟bNab对艾滋病毒覆盖率的动态统计来解决这个复杂的问题。这一分析引入了一个关键的、与时间尺度相关的竞争：为了保护，bNab必须在足够的化学计量比下积累，以便在病毒粒子穿透CVM并到达目标细胞之前中和HIV。我们开发了一个模型，该模型包含了HIV和bNab在精液和精液中的浓度和扩散系数，选择的bNab的结合(Kon)和解离(Koff)的动力学速率，以及与生理相关的Cvm和精液层的厚度。全面的模型模拟得出了关于CVM中和动力学的可靠结论。首先，由于精液中的病毒粒子需要穿透CVM的时间有限，CVM中必须存在比体外估计的更高的bNab浓度才能中和HIV。其次，该模型预测bNab具有更快的kon，几乎独立于koff，应该在体内提供更强的中和效力。这些发现表明，到达目标细胞最快的病毒粒子感染的可能性最大。这也意味着许多新近发现的bNab在体外中和效力的显著改善可能不会转化为提供对初始阴道感染的保护所需的bNab剂量的相应减少。我们的建模框架提供了一个有价值的工具，以获得对针对HIV和其他传染病的粘膜免疫动态的定量洞察。
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.
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影响因子：
3.8
作者：
Chakraborty, H;Sen, PK;Cohen, MS
通讯作者：
Cohen, MS
影响因子：
3.4
作者：
Geonnotti, Anthony R.;Katz, David F.
通讯作者：
Katz, David F.
DOI：
10.1126/science.1175868
发表时间：
2009-11-20
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
Chen L;Kwon YD;Zhou T;Wu X;O'Dell S;Cavacini L;Hessell AJ;Pancera M;Tang M;Xu L;Yang ZY;Zhang MY;Arthos J;Burton DR;Dimitrov DS;Nabel GJ;Posner MR;Sodroski J;Wyatt R;Mascola JR;Kwong PD
通讯作者：
Kwong PD
DOI：
10.1126/science.1213782
发表时间：
2011-12-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Diskin R;Scheid JF;Marcovecchio PM;West AP Jr;Klein F;Gao H;Gnanapragasam PN;Abadir A;Seaman MS;Nussenzweig MC;Bjorkman PJ
通讯作者：
Bjorkman PJ
影响因子：
5.4
作者：
Lai, Samuel K.;Hida, Kaoru;Hanes, Justin
通讯作者：
Hanes, Justin