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

最近，针对HIV-1的强效、广泛中和抗体的发展，激发了人们对被动免疫策略的兴趣，以预防、治疗和根除HIV感染。非人灵长类动物的研究表明，中和抗体可以防止全身感染，这是通过血液和血清转化中可检测到的病毒RNA水平来定义的。然而，这并不能揭示病毒在被控制之前是否在暴露的粘膜或引流淋巴结中复制。如果是这样，就会产生潜伏感染的细胞，当抗体浓度超过保护水平时，可能会产生反应性病毒。在中和抗体保护全身感染的情况下，在粘膜暴露后早期在远端部位检测感染性病毒，这引起了人们的怀疑，即中和抗体是否能完全防止第一个细胞被HIV感染，从而提供最严格意义上的消毒免疫。因此，在之前的资助期间，我们开发了一种新的挑战病毒，它在第一次感染周期中使用HIV-1 Env进入，但在随后的所有回合中转换为SIV Env。由于SIV Env不被我们研究中使用的HIV Env抗体识别，这种HIV抗体介导的保护一定是由于阻断第一个细胞的感染。在非人灵长类动物中使用传统的低剂量和新型同时高剂量的直肠攻击，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，证明抗体可以在粘膜接触任何病毒后提供最严格意义上的消毒免疫。同时进行的高剂量攻击也可以量化第一个细胞的感染被阻断的效率，结果显示HIV抗体将第一个细胞的感染事件减少了60倍以上。在人类自然低剂量暴露后，首次感染事件数量的减少应该会大大降低感染的概率，从而提供针对HIV-1的消毒免疫。我们还观察到，在HIV抗体与病毒粒子结合而不中和病毒粒子的条件下，首次感染事件减少了4.6倍。由于阻断第一个细胞的感染应该是最好的保护方式，并且由于在最严格意义上提供绝育免疫的效应机制可能不同于在后续步骤中控制病毒复制所需的机制，因此需要更好地了解阻断第一个细胞感染的机制。因此，在下一个资助期，我们建议通过中和和非中和机制确定fc效应物功能与预防第一个细胞感染的相关性。此外，将探讨进入的病毒粒子的调理程度对防止第一个细胞感染的影响。

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.