Titti Fausto, Maggiorella Maria T, Ferrantelli Flavia, Sernicola Leonardo, Bellino Stefania, Collacchi Barbara, Fanales Belasio Emanuele, Moretti Sonia, Pavone Cossut Maria Rosaria, Belli Roberto, Olivieri Erika, Farcomeni Stefania, Compagnoni Daniela, Michelini Zuleika, Sabbatucci Michela, Sparnacci Katia, Tondelli Luisa, Laus Michele, Cafaro Aurelio, Caputo Antonella, Ensoli Barbara
National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.
Department of Environmental and Live Science, University of East Piemonte, Alessandria, Italy.
PLoS One. 2014 Oct 30;9(10):e111360. doi: 10.1371/journal.pone.0111360. eCollection 2014.
Here we describe a prime-boost regimen of vaccination in Macaca fascicularis that combines priming with novel anionic microspheres designed to deliver the biologically active HIV-1 Tat protein and boosting with Tat in Alum. This regimen of immunization modulated the IgG subclass profile and elicited a balanced Th1-Th2 type of humoral and cellular responses. Remarkably, following intravenous challenge with SHIV89.6Pcy243, vaccinees significantly blunted acute viremia, as compared to control monkeys, and this control was associated with significantly lower CD4+ T cell depletion rate during the acute phase of infection and higher ability to resume the CD4+ T cell counts in the post-acute and chronic phases of infection. The long lasting control of viremia was associated with the persistence of high titers anti-Tat antibodies whose profile clearly distinguished vaccinees in controllers and viremics. Controllers, as opposed to vaccinated and viremic cynos, exhibited significantly higher pre-challenge antibody responses to peptides spanning the glutamine-rich and the RGD-integrin-binding regions of Tat. Finally, among vaccinees, titers of anti-Tat IgG1, IgG3 and IgG4 subclasses had a significant association with control of viremia in the acute and post-acute phases of infection. Altogether these findings indicate that the Tat/H1D/Alum regimen of immunization holds promise for next generation vaccines with Tat protein or other proteins for which maintenance of the native conformation and activity are critical for optimal immunogenicity. Our results also provide novel information on the role of anti-Tat responses in the prevention of HIV pathogenesis and for the design of new vaccine candidates.
在此，我们描述了一种食蟹猴的初免 - 加强免疫接种方案，该方案将初免与设计用于递送具有生物活性的HIV - 1 Tat蛋白的新型阴离子微球相结合，并使用明矾佐剂中的Tat进行加强免疫。这种免疫方案调节了IgG亚类谱，并引发了平衡的Th1 - Th2型体液和细胞反应。值得注意的是，在用SHIV89.6Pcy243进行静脉攻击后，与对照猴子相比，疫苗接种者显著降低了急性病毒血症，并且这种控制与感染急性期CD4 + T细胞耗竭率显著降低以及在感染的急性后期和慢性期恢复CD4 + T细胞计数的能力提高有关。病毒血症的长期控制与高滴度抗Tat抗体的持续存在有关，其特征明显区分了病毒控制者和病毒血症者。与接种疫苗且出现病毒血症的食蟹猴相比，病毒控制者在攻击前对跨越Tat富含谷氨酰胺区域和RGD - 整合素结合区域的肽表现出显著更高的抗体反应。最后，在疫苗接种者中，抗Tat IgG1、IgG3和IgG4亚类的滴度与感染急性期和急性后期的病毒血症控制有显著关联。总之，这些发现表明，Tat/H1D/明矾免疫方案有望用于下一代以Tat蛋白或其他对天然构象和活性的维持对最佳免疫原性至关重要的蛋白质为基础的疫苗。我们的结果还提供了关于抗Tat反应在预防HIV发病机制中的作用以及新型疫苗候选物设计的新信息。
