Hidajat Rachmat, Xiao Peng, Zhou Qifeng, Venzon David, Summers L Ebonita, Kalyanaraman Vaniambadi S, Montefiori David C, Robert-Guroff Marjorie
Vaccine Branch, National Cancer Institute, Bethesda, Maryland 20892-5065, USA.
J Virol. 2009 Jan;83(2):791-801. doi: 10.1128/JVI.01672-08. Epub 2008 Oct 29.
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 SIV(mac251) 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 SIV(mac251) 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.
细胞介导的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明确。此前，我们报道，用具有复制能力的5型腺病毒宿主范围突变体（Ad5hr）-SIV重组体进行序贯口服/口服或鼻内/口服（I/O）启动，随后进行肌肉内包膜蛋白加强免疫，可引发全身和黏膜细胞免疫，并在直肠感染SIV（mac251）后使慢性病毒血症显著同等程度降低。然而，I/O启动对急性病毒血症的控制效果明显更好。在此，研究了全身和黏膜体液免疫与急性攻击结果之间的潜在关联。两组均诱导出针对SIV（mac251）的强血清结合但非中和抗体反应。I/O组的抗体反应出现更早且总体更高。急性病毒血症的降低与更高的血清结合滴度、更强的抗体依赖性细胞毒性活性以及攻击前峰值和攻击后2周的抗体依赖性细胞介导的病毒抑制（ADCVI）显著相关。I/O组在支气管肺泡灌洗中始终表现出更强的抗包膜免疫球蛋白A（IgA）抗体反应，并且在攻击后2周直肠抗包膜IgA回忆反应更强。攻击前后的直肠分泌物均抑制SIV跨上皮细胞的转胞吞作用。I/O组的抑制作用明显更高，尽管未达到与急性病毒血症降低的显著相关性。总体而言，复制型Ad5hr-SIV启动/包膜加强免疫方法引发了具有多种功能活性的强大全身和黏膜抗体。I/O组免疫反应升高的模式与其对急性病毒血症更好的控制一致，这至少部分是由ADCVI活性和转胞吞作用抑制介导的。
