Live simian immunodeficiency virus vaccine correlate of protection: immune complex-inhibitory Fc receptor interactions that reduce target cell availability.
Live simian immunodeficiency virus vaccine correlate of protection: immune complex-inhibitory Fc receptor interactions that reduce target cell availability.
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DOI：
10.4049/jimmunol.1400822
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发表时间：
2014-09-15
期刊：
影响因子：
--
通讯作者：
Haase AT
中科院分区：
文献类型：
--
作者：
Smith AJ;Wietgrefe SW;Shang L;Reilly CS;Southern PJ;Perkey KE;Duan L;Kohler H;Müller S;Robinson J;Carlis JV;Li Q;Johnson RP;Haase AT
非常需要指导设计有效艾滋病毒疫苗的原则，特别是为了保护非洲大流行病中心的妇女。我们一直在通过在HIV-1传播给女性的SIV-恒河猴动物模型中鉴定与SIVmac 239 Δnef疫苗接种相关的稳健保护的相关性来寻求这些原则。我们已经确定了SIVmac 239 Δnef对阴道攻击的保护作用的一个相关性，作为SIV-gp 41三聚体抗体产生的驻留粘膜系统，以及新生儿Fc受体（FcRn）介导的这些抗体在病毒进入路径上的浓度，以抑制在进入口建立感染的创始者群体。在这里，我们确定了第二个保护相关性，阻断CD 4 + T细胞募集，以抑制感染的创始人群体的局部扩张。病毒特异性免疫复合物与子宫颈内衬上皮中的抑制性FcγRIIb受体相互作用，启动基因表达，阻断靶细胞募集以促进局部扩增。粘膜前线的免疫复合物-Fc γRIIb受体相互作用抑制了对阴道激发的先天免疫应答，这可能是粘膜免疫系统感知和调节对先前遇到的病原体应答的潜在一般机制。设计疫苗以提供保护而不引发这些促进传播的先天反应可能有助于开发有效的HIV-1疫苗。
Principles to guide design of an effective vaccine against HIV are greatly needed, particularly to protect women in the pandemic’s epicentre in Africa. We have been seeking these principles by identifying correlates of the robust protection associated with SIVmac239Δnef vaccination in the SIV-rhesus macaque animal model of HIV-1 transmission to women. We have identified one correlate of SIVmac239Δnef protection against vaginal challenge as a resident mucosal system for SIV-gp41 trimer antibody production and neonatal Fc receptor (FcRn)-mediated concentration of these antibodies on the path of virus entry to inhibit establishment of infected founder populations at the portal of entry. Here we identify as a second protection correlate, blocking CD4+ T cell recruitment to inhibit local expansion of infected founder populations. Virus-specific immune complex interactions with the inhibitory FcγRIIb receptor in the epithelium lining the cervix initiate expression of genes that block recruitment of target cells to fuel local expansion. Immune complex-FcγRIIb receptor interactions at mucosal frontlines to dampen the innate immune response to vaginal challenge could be a potentially general mechanism for the mucosal immune system to sense and modulate the response to a previously encountered pathogen. Designing vaccines to provide protection without eliciting these transmission-promoting innate responses could contribute to developing an effective HIV-1 vaccine.
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