Correlation of Vaccine-Elicited Systemic and Mucosal Nonneutralizing Antibody Activities with Reduced Acute Viremia following Intrarectal Simian Immunodeficiency Virus SIVmac251 Challenge of Rhesus Macaques
Correlation of Vaccine-Elicited Systemic and Mucosal Nonneutralizing Antibody Activities with Reduced Acute Viremia following Intrarectal Simian Immunodeficiency Virus SIVmac251 Challenge of Rhesus Macaques
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DOI：
10.1128/jvi.01672-08
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发表时间：
2009-01-15
影响因子：
5.4
通讯作者：
Robert-Guroff, Marjorie
中科院分区：
文献类型：
--
作者：
Hidajat, Rachmat;Xiao, Peng;Robert-Guroff, Marjorie
细胞免疫和中和抗体有助于控制人类免疫缺陷病毒/猴免疫缺陷病毒(HIV/SIV)感染，但非中和抗体的作用尚未确定。此前，我们曾报道，在直肠SIVmac251攻击后，用可复制的腺病毒5型宿主范围突变体(Ad5hr)-SIV重组体(Ad5hr)-SIV重组体序贯口服/口服或鼻腔/口服(I/O)，然后肌肉内包膜蛋白增强，可诱导系统和粘膜细胞免疫，并显示出同等显著的慢性病毒血症减少。然而，I/O启动显著改善了对急性病毒血症的控制。在这里，系统和粘膜体液免疫与急性发作结局的潜在相关性进行了研究。两组均诱导出较强的抗SIVmac251的血清结合但非中和抗体反应。I/O组出现抗体反应较早，总体较高。急性病毒血症的减少与更高的血清结合滴度、更强的抗体依赖细胞毒活性以及攻击前和攻击后2周抗体依赖细胞介导的病毒抑制(ADCVI)峰值显著相关。2周后，I/O组小鼠支气管肺泡灌洗液中抗包膜免疫球蛋白A(IgA)抗体反应持续增强，直肠抗包膜免疫球蛋白A(IgA)记忆反应增强。挑战前后的直肠分泌物抑制了SIV跨上皮细胞的细胞转运。这种抑制在I/O组明显更高，尽管与急性病毒血症的减少没有达到显著的相关性。总体而言，复制的Ad5hr-SIV启动/包膜增强方法诱导了具有多种功能活性的强大的系统和粘膜抗体。I/O组免疫反应增强的模式与其对急性病毒血症的较好控制是一致的，至少部分是由ADCVI活性和跨细胞抑制介导的。
Cell-mediated immunity and neutralizing antibodies contribute to control of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) infection, but the role of nonneutralizing antibodies is not defined. Previously, we reported that sequential oral/oral or intranasal/oral (I/O) priming with replication-competent adenovirus type 5 host range mutant (Ad5hr)-SIV recombinants, followed by intramuscular envelope protein boosting, elicited systemic and mucosal cellular immunity and exhibited equivalent, significant reductions of chronic viremia after rectal SIVmac251 challenge. However, I/O priming gave significantly better control of acute viremia. Here, systemic and mucosal humoral immunity were investigated for potential correlates with the acute challenge outcome. Strong serum binding but nonneutralizing antibody responses against SIVmac251 were induced in both groups. Antibody responses appeared earlier and overall were higher in the I/O group. Reduced acute viremia was significantly correlated with higher serum binding titer, stronger antibody-dependent cellular cytotoxicity activity, and peak prechallenge and 2-week-postchallenge antibody-dependent cell-mediated viral inhibition (ADCVI). The I/O group consistently displayed greater anti-envelope immunoglobulin A (IgA) antibody responses in bronchoalveolar lavage and a stronger rectal anti-envelope IgA anamnestic response 2 weeks postchallenge. Pre- and postchallenge rectal secretions inhibited SIV transcytosis across epithelial cells. The inhibition was significantly higher in the I/O group, although a significant correlation with reduced acute viremia was not reached. Overall, the replicating Ad5hr-SIV priming/envelope boosting approach elicited strong systemic and mucosal antibodies with multiple functional activities. The pattern of elevated immune responses in the I/O group is consistent with its better control of acute viremia mediated, at least in part, by ADCVI activity and transcytosis inhibition.