HIV-1 gp120与有效病毒亚单位疫苗诱导Tfh细胞活化及抗体生成能力的比较研究

The cause of the HIV vaccines in clinical experiment could not protect the indivials is unknown. One of the important questions is how the nature of specific host immune responses influences the control of viral infection and vaccine in HIV infection is still unclear,which is an obstacle for HIV-1 vaccine design. The first domain in CD4 which is contribute to bind with HIV-1, furthermore, D1 also is the key domain for CD4 and MHC-II binding. The previous research showed that deletion of the CD4 binding sites of gp120 could improve the specific antibodies level. We propose a hypothesis that the binding between HIV-1 gp120 and CD4 can inhibit the interaction between CD4 and MHC II, which interferes in the activation of Tfh cells and protective antibodies eliciting. The immunization experiments indicated that the priming of Th2-biased immune responses may be protective against HBV or HPV infection. Vaccines based on proteins may preferentially induce Th2-biased immune responses. This research could find the different in antigen presentation, function of Tfh, differenciation of B cells and formation of plasma cells between HIV-1, HBsAg and HPV-L1. This research could reveal the differenciation in HIV gp120 and other effective subunit vaccines. this research could provide a new way to enhance the capability of antibody induced by HIV-1 gp120 to develop an effective vaccine.

HIV疫苗临床实验数次失败的原因至今不明，国际上对HIV感染和疫苗诱导的免疫防御机制还知之甚少。HIV包膜gp120与CD4第一结构域相结合，介导病毒侵入靶细胞，该区域也是CD4与MHC II分子结合的功能区。本课题组前期发现，消除gp120上CD4结合位点，显著提高了包膜特异性抗体水平。因此，我们提出假设：与有效亚单位疫苗相比，HIV gp120因和CD4结合，抑制了辅助性T细胞功能，导致难以获得理想的保护作用。HBV S蛋白(HBsAg)和HPV-L1蛋白疫苗的保护性作用主要以诱导体液免疫为主，介导体液免疫的辅助性T细胞起关键作用。本研究将在国际上首次通过比较gp120与HBsAg及HPV-L1在免疫呈递、Tfh细胞功能、诱导B细胞分化和浆细胞形成等方面的差异，明确gp120与有效的亚单位疫苗诱导抗体产生能力的差异机制,为提高HIV-1包膜诱导保护性抗体产生能力提供创新思路。

HIV疫苗临床实验失败表明，其不能有效刺激机体产生高滴度的保护性抗体，其原因至今不明确。HBV S蛋白(HBsAg) 蛋白疫苗的保护性作用主要以诱导体液免疫为主。本研究通过比较HBsAg和HIV-1 gp120蛋白免疫后诱导淋巴细胞增殖、Tfh细胞的功能、生发中心B细胞的活化以及抗体产生能力等方面的差异，来分析gp120与有效亚单位疫苗诱导抗体产生能力差异的机制。结果发现HBsAg比HIV-1 gp120能够诱导良好的早期淋巴细胞增殖反应。已知PD-1是一种重要的免疫抑制分子，能对免疫反应起负性调节作用。我们发现HIV-1 gp120免疫后会激活PD-1高表达的T淋巴细胞群，而HBsAg免疫后没有激活该细胞群。HBsAg和HIV-1 gp120相比，其加强免疫虽然早期没有产生高水平的Tfh细胞，但是产生良好的生发中心B细胞反应。骨髓淋巴细胞分泌抗体浆细胞数量及产生抗体水平均显示HBsAg能够诱导产生高水平特异性抗体，但HIV-1 gp120产生了过多的非特异性抗体。通过观察早期抗体回忆反应的能力，还发现HBsAg在加强免疫后的较短时间内就可产生滴度较高的特异性抗体，而HIV-1 gp120在多次免疫后才能够产生高低度抗体。本研究结果为提高HIV-1包膜诱导保护性抗体产生能力提供创新思路。