Relevance of Fc-effector functions for prevention of infection of the first cell in the HIV nonhuman primate model

针对HIV-1的有效的、广泛中和的抗体的最新发展激发了对预防、治疗和根除HIV感染的被动免疫策略的兴趣。非人灵长类动物研究表明，中和抗体可以预防全身性感染，如血液中可检测水平的病毒RNA和血清转化所定义的。然而，这并不能揭示病毒是否在暴露的粘膜或引流淋巴结中复制。如果是这种情况，潜伏感染的细胞产生，这可能是反应性的病毒时，抗体浓度已超过保护水平下降。在粘膜暴露后早期，在存在保护免受全身感染的中和抗体的情况下，在远端部位检测到感染性病毒，这引起了人们对中和抗体是否能够完全防止HIV感染第一个细胞并因此提供最严格意义上的杀菌免疫的怀疑。因此，在上一个资助期间，我们开发了一种新型的挑战病毒，在第一个感染周期中使用HIV-1 Env进入，但随后在所有后续轮中切换到SIV Env。由于SIV Env不被我们研究中使用的HIV Env抗体识别，因此这种HIV抗体介导的保护作用一定是由于阻断了第一个细胞的感染。在非人灵长类动物中使用传统的低剂量和新型的同时高剂量直肠攻击，我们观察到对新型攻击病毒感染的保护。据我们所知，这是第一个直接证据，表明抗体可以在粘膜暴露于任何病毒后提供最严格意义上的杀菌免疫。同时进行的高剂量挑战也可以量化第一个细胞的感染被阻断的效率，结果表明HIV抗体将第一个细胞的感染事件减少了60倍以上。在人体自然低剂量暴露后，首次感染事件数量的减少应大大降低感染的可能性，从而提供针对HIV-1的杀菌免疫。我们还观察到，在一定条件下，由于阻断第一个细胞的感染应该是最好的保护方式，并且由于在最严格的意义上提供杀菌免疫的效应机制可能不同于在随后步骤中控制病毒复制所需的机制，因此更好地理解阻断第一个细胞的感染的机制是必要的。感染第一个细胞是必需的。因此，对于下一个资助期，我们建议确定Fc效应子功能对于通过中和和非中和机制预防第一细胞感染的相关性。此外，将探索进入的病毒粒子的调理作用程度对预防第一细胞感染的影响。

The recent development of potent, broadly-neutralizing antibodies against HIV-1 has fueled interest in passive immunization strategies to prevent, treat, and eradicate HIV infection. Non-human primate studies have shown, that neutralizing antibodies can prevent systemic infection as defined by detectable levels of viral RNA in the blood and seroconversion. However, this does not reveal whether the virus replicates in the exposed mucosa or draining lymph nodes before it is contained. If this were the case, latently infected cells are generated, that may reactive virus when antibody concentrations have fallen beyond protective levels. Detection of infectious virus at distal sites early after mucosal exposure in the presence of a neutralizing antibody protecting from systemic infection has raised doubts whether neutralizing antibodies can prevent infection of the first cell by HIV at all and thus provide sterilizing immunity in the strictest sense. During the previous funding period, we have therefore developed a novel challenge virus, that uses HIV-1 Env for entry during the first infection cycle, but then switches to SIV Env for all subsequent rounds. Since SIV Env is not recognized by the HIV Env antibody used in our study, protection mediated by this HIV antibody must be due to blocking infection of the first cell. Using a conventional low-dose and a novel simultaneous high-dose rectal challenge in non-human primates, we observed protection from infection with the novel challenge virus. To the best of our knowledge, this is the first direct evidence that antibodies can provide sterilizing immunity in the strictest sense after mucosal exposure to any virus. The simultaneous high dose challenge, which also allowed to quantify how efficiently infection of the first cell is blocked, revealed that the HIV antibody reduced the number of infection events of the first cell more than 60-fold. After natural low-dose exposure in humans, such a reduction in the number of first infection events should greatly reduce the probability of infection and thus provide sterilizing immunity against HIV-1. We also observed a 4.6-fold reduction of first infection events under conditions, in which the HIV antibody bound to the virion without neutralizing it. Since blocking infection of the first cell should be the best way of protection and since effector mechanisms providing sterilizing immunity in the strictest sense may differ from those required for control of virus replication at subsequent steps a better understanding of mechanisms blocking infection of the first cell, is needed. For the next funding period we therefore propose to determine the relevance of Fc-effector functions for prevention of infection of the first cell by neutralization and non-neutralizing mechanisms. In addition, the influence of the extent of opsonisation of the incoming virion for preventing infection of the first cell will be explored.