Koopman Gerrit, Mooij Petra, Dekking Liesbeth, Mortier Daniëlla, Nieuwenhuis Ivonne G, van Heteren Melanie, Kuipers Harmjan, Remarque Edmond J, Radošević Katarina, Bogers Willy M J M
Department of Virology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
Department of Virology, Biomedical Primate Research Centre, Rijswijk, The Netherlands
J Virol. 2015 Nov 4;90(2):1023-33. doi: 10.1128/JVI.02757-15. Print 2016 Jan 15.
Influenza virus infection of nonhuman primates is a well-established animal model for studying pathogenesis and for evaluating prophylactic and therapeutic intervention strategies. However, usually a standard dose is used for the infection, and there is no information on the relation between challenge dose and virus replication or the induction of immune responses. Such information is also very scarce for humans and largely confined to evaluation of attenuated virus strains. Here, we have compared the effect of a commonly used dose (4 × 10(6) 50% tissue culture infective doses) versus a 100-fold-higher dose, administered by intrabronchial installation, to two groups of 6 cynomolgus macaques. Animals infected with the high virus dose showed more fever and had higher peak levels of gamma interferon in the blood. However, virus replication in the trachea was not significantly different between the groups, although in 2 out of 6 animals from the high-dose group it was present at higher levels and for a longer duration. The virus-specific antibody response was not significantly different between the groups. However, antibody enzyme-linked immunosorbent assay, virus neutralization, and hemagglutination inhibition antibody titers correlated with cumulative virus production in the trachea. In conclusion, using influenza virus infection in cynomolgus macaques as a model, we demonstrated a relationship between the level of virus production upon infection and induction of functional antibody responses against the virus.
There is only very limited information on the effect of virus inoculation dose on the level of virus production and the induction of adaptive immune responses in humans or nonhuman primates. We found only a marginal and variable effect of virus dose on virus production in the trachea but a significant effect on body temperature. The induction of functional antibody responses, including virus neutralization titer, hemagglutination inhibition titer, and antibody-dependent cell-mediated cytotoxicity, correlated with the level of virus replication measured in the trachea. The study reveals a relationship between virus production and functional antibody formation, which could be relevant in defining appropriate criteria for new influenza virus vaccine candidates.
非人灵长类动物的流感病毒感染是用于研究发病机制以及评估预防和治疗干预策略的成熟动物模型。然而，通常使用标准剂量进行感染，且尚无关于攻击剂量与病毒复制或免疫反应诱导之间关系的信息。此类信息在人类中也非常稀少，并且很大程度上局限于对减毒病毒株的评估。在此，我们通过支气管内接种，将常用剂量（4×10⁶ 50%组织培养感染剂量）与高100倍的剂量分别给予两组6只食蟹猴，比较了二者的效果。感染高病毒剂量的动物发热更明显，血液中γ干扰素的峰值水平更高。然而，两组之间气管中的病毒复制并无显著差异，尽管高剂量组的6只动物中有2只其病毒水平更高且持续时间更长。两组之间病毒特异性抗体反应并无显著差异。然而，抗体酶联免疫吸附测定、病毒中和及血凝抑制抗体滴度与气管中累积病毒产生相关。总之，以食蟹猴的流感病毒感染为模型，我们证明了感染时病毒产生水平与针对该病毒的功能性抗体反应诱导之间的关系。
关于病毒接种剂量对人类或非人灵长类动物病毒产生水平及适应性免疫反应诱导的影响，仅有非常有限的信息。我们发现病毒剂量对气管中病毒产生仅有微小且可变的影响，但对体温有显著影响。包括病毒中和滴度、血凝抑制滴度及抗体依赖性细胞介导的细胞毒性在内的功能性抗体反应诱导与气管中测量的病毒复制水平相关。该研究揭示了病毒产生与功能性抗体形成之间的关系，这可能与确定新型流感病毒疫苗候选物的适当标准相关。
