Institute of Medical Virology, University of Zurich, Switzerland; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
Institute of Medical Virology, University of Zurich, Switzerland.
Virus Res. 2016 Jun 15;218:57-70. doi: 10.1016/j.virusres.2015.10.009. Epub 2015 Oct 19.
Broadly neutralizing antibodies against human immunodeficiency virus type 1 (HIV-1) are considered vital components of novel therapeutics and blueprints for vaccine research. Yet escape to even the most potent of these antibodies is imminent in natural infection. Measures to define antibody efficacy and prevent mutant selection are thus urgently needed. Here, we derive a mathematical framework to predict the concentration ranges for which antibody escape variants can outcompete their viral ancestors, referred to as mutant selection window (MSW). When determining the MSW, we focus on the differential efficacy of neutralizing antibodies against HIV-1 in two canonical infection routes, free-virus infection and cell-cell transmission. The latter has proven highly effective in vitro suggesting its importance for both in vivo spread as well as for escaping targeted intervention strategies. We observed a range of MSW patterns that highlight the potential of mutants to arise in both transmission pathways and over wide concentration ranges. Most importantly, we found that only when the arising mutant has both, residual sensitivity to the neutralizing antibody and reduced infectivity compared to the parental virus, antibody dosing outside of the MSW to restrict mutant selection is possible. Emergence of mutants that provide complete escape and have no considerable fitness loss cannot be prevented by adjusting antibody doses. The latter may in part explain the ubiquitous resistance to neutralizing antibodies observed in natural infection and antibody treatment. Based on our findings, combinations of antibodies targeting different epitopes should be favored for antibody-based interventions as this may render complete resistance less likely to occur and also increase chances that multiple escapes result in severe fitness loss of the virus making longer-term antibody treatment more feasible.
广谱中和抗体对人类免疫缺陷病毒 1 型（HIV-1）的抑制作用被认为是新型治疗药物的重要组成部分，也是疫苗研究的蓝图。然而，在自然感染中，即使是最有效的抗体也会产生逃逸。因此，迫切需要采取措施来定义抗体的疗效并防止突变体的选择。在这里，我们提出了一个数学框架来预测抗体逃逸变体可以与它们的病毒祖先竞争的浓度范围，称为突变选择窗（MSW）。在确定 MSW 时，我们专注于中和抗体对 HIV-1 在两种典型感染途径中的效力差异，即游离病毒感染和细胞间传播。后者在体外已被证明非常有效，这表明它对体内传播以及逃避靶向干预策略都很重要。我们观察到一系列 MSW 模式，这些模式突出了在两种传播途径中以及在广泛的浓度范围内产生突变体的潜力。最重要的是，我们发现只有当出现的突变体具有对中和抗体的残余敏感性以及与亲本病毒相比降低的感染性时，才有可能在 MSW 之外进行抗体剂量给药以限制突变体的选择。对于调整抗体剂量，无法防止出现具有完全逃逸能力且没有明显适应性损失的突变体。后者可能部分解释了在自然感染和抗体治疗中观察到的普遍对中和抗体的抗性。基于我们的发现，应优先考虑针对不同表位的抗体组合进行基于抗体的干预，因为这可能使完全耐药的发生可能性降低，并增加多个逃逸导致病毒严重适应性损失的机会，从而使长期抗体治疗更加可行。
