Yu Hao-Tong, Tian Dan, Wang Jia-Ye, Guo Cai-Xia, Li Yan, Wang Xin, Li Di, Zhang Feng-Min, Zhuang Min, Ling Hong
Department of Microbiology, Harbin Medical University, Harbin, China.
Department of Microbiology, Harbin Medical University, Harbin, China; Heilongjiang Provincial Key Lab for Infection and Immunity, Key Lab of Etiology of Heilongjiang Province Education Bureau, Harbin, China.
PLoS One. 2014 Dec 29;9(12):e115047. doi: 10.1371/journal.pone.0115047. eCollection 2014.
The CD4 binding site (CD4BS) of the HIV-1 envelope glycoprotein (Env) contains epitopes for broadly neutralizing antibody (nAb) and is the target for the vaccine development. However, the CD4BS core including residues 425-430 overlaps the B cell superantigen site and may be related to B cell exhaustion in HIV-1 infection. Furthermore, production of nAb and high-affinity plasma cells needs germinal center reaction and the help of T follicular helper (Tfh) cells. We believe that strengthening the ability of Env CD4BS in inducing Tfh response and decreasing the effects of the superantigen are the strategies for eliciting nAb and development of HIV-1 vaccine. We constructed a gp120 mutant W427S of an HIV-1 primary R5 strain and examined its ability in the elicitation of Ab and the production of Tfh by immunization of BALB/c mice. We found that the trimeric wild-type gp120 can induce more non-specific antibody-secreting plasma cells, higher serum IgG secretion, and more Tfh cells by splenocyte. The modified W427S gp120 elicits higher levels of specific binding antibodies as well as nAbs though it produces less Tfh cells. Furthermore, higher Tfh cell frequency does not correlate to the specific binding Abs or nAbs indicating that the wild-type gp120 induced some non-specific Tfh that did not contribute to the production of specific Abs. This gp120 mutant led to more memory Tfh production, especially, the effector memory Tfh cells. Taken together, W427S gp120 could induce higher level of specific binding and neutralizing Ab production that may be associated with the reduction of non-specific Tfh but strengthening of the memory Tfh.
HIV-1包膜糖蛋白（Env）的CD4结合位点（CD4BS）包含广泛中和抗体（nAb）的表位，是疫苗开发的靶点。然而，包括425-430位残基的CD4BS核心与B细胞超抗原位点重叠，可能与HIV-1感染中的B细胞耗竭有关。此外，nAb和高亲和力浆细胞的产生需要生发中心反应和滤泡辅助性T（Tfh）细胞的帮助。我们认为，增强Env CD4BS诱导Tfh反应的能力并降低超抗原的影响是引发nAb和开发HIV-1疫苗的策略。我们构建了一株HIV-1原始R5毒株的gp120突变体W427S，并通过免疫BALB/c小鼠来检测其诱导抗体产生及Tfh细胞生成的能力。我们发现，三聚体野生型gp120可诱导更多非特异性抗体分泌浆细胞、更高的血清IgG分泌以及更多的脾细胞Tfh细胞。修饰后的W427S gp120虽然产生的Tfh细胞较少，但能引发更高水平的特异性结合抗体以及nAb。此外，较高的Tfh细胞频率与特异性结合抗体或nAb并无关联，这表明野生型gp120诱导了一些对特异性抗体产生无贡献的非特异性Tfh。这种gp120突变体导致更多记忆性Tfh产生，尤其是效应记忆性Tfh细胞。综上所述，W427S gp120可诱导更高水平的特异性结合和中和抗体产生，这可能与非特异性Tfh的减少但记忆性Tfh的增强有关。
