The grafting of universal T-helper epitopes enhances immunogenicity of HIV-1 Tat concurrently improving its safety profile.
The grafting of universal T-helper epitopes enhances immunogenicity of HIV-1 Tat concurrently improving its safety profile.
复制标题
DOI：
10.1371/journal.pone.0114155
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Ranga U
中科院分区：
文献类型：
--
作者：
Kashi VP;Jacob RA;Shamanna RA;Menon M;Balasiddaiah A;Varghese RK;Bachu M;Ranga U
细胞外Tat(Etat)在HIV-1的致病过程中起重要作用。抗TAT抗体的存在与疾病进展呈负相关，因此使TAT成为潜在的候选疫苗。然而，TAT的细胞毒性和适度的免疫原性仍然是开发基于TAT的疫苗的障碍。在这里，我们报告了一种新的策略，以同时增强TAT的免疫原性和安全性。将通用辅助性T淋巴细胞(HTL)表位PAN DR表位(PADRE)和Pol711分别嫁接到富含半胱氨酸结构域(CRD)和碱性结构域(BD)上，消除了TAT蛋白的反式激活潜能。与野生型TAT相比，HTL-TAT蛋白在BALB/c小鼠中产生了显著更高的抗体滴度。在HTL-TAT免疫中，虽然N端表位仍然是免疫优势表位，但在外显子2中发现了一个与之相当的表位，这表明有更广泛的免疫识别。此外，HTL-TAT蛋白诱导了高亲和力的交叉反应抗体，有效地中和了外源TAT，从而阻止了TAT缺陷前病毒的激活。这种方法具有呈现多个B细胞表位、增强抗体反应和重要的反式激活缺陷TAT蛋白等优点，在基于TAT的HIV/AIDS疫苗的研制中具有潜在的应用前景。
Extracellular Tat (eTat) plays an important role in HIV-1 pathogenesis. The presence of anti-Tat antibodies is negatively correlated with disease progression, hence making Tat a potential vaccine candidate. The cytotoxicity and moderate immunogenicity of Tat however remain impediments for developing Tat-based vaccines. Here, we report a novel strategy to concurrently enhance the immunogenicity and safety profile of Tat. The grafting of universal helper T-lymphocyte (HTL) epitopes, Pan DR Epitope (PADRE) and Pol711 into the cysteine rich domain (CRD) and the basic domain (BD) abolished the transactivation potential of the Tat protein. The HTL-Tat proteins elicited a significantly higher titer of antibodies as compared to the wild-type Tat in BALB/c mice. While the N-terminal epitope remained immunodominant in HTL-Tat immunizations, an additional epitope in exon-2 was recognized with comparable magnitude suggesting a broader immune recognition. Additionally, the HTL-Tat proteins induced cross-reactive antibodies of high avidity that efficiently neutralized exogenous Tat, thus blocking the activation of a Tat-defective provirus. With advantages such as presentation of multiple B-cell epitopes, enhanced antibody response and importantly, transactivation-deficient Tat protein, this approach has potential application for the generation of Tat-based HIV/AIDS vaccines.
登录
查看更多内容
DOI：
10.1073/pnas.070049797
发表时间：
2000-03-28
影响因子：
11.1
作者：
Pauza, CD;Trivedi, P;Gallo, RC
通讯作者：
Gallo, RC
影响因子：
64.8
作者：
Hansen, Scott G.;Ford, Julia C.;Lewis, Matthew S.;Ventura, Abigail B.;Hughes, Colette M.;Coyne-Johnson, Lia;Whizin, Nathan;Oswald, Kelli;Shoemaker, Rebecca;Swanson, Tonya;Legasse, Alfred W.;Chiuchiolo, Maria J.;Parks, Christopher L.;Axthelm, Michael K.;Nelson, Jay A.;Jarvis, Michael A.;Piatak, Michael, Jr.;Lifson, Jeffrey D.;Picker, Louis J.
通讯作者：
Picker, Louis J.
影响因子：
6.4
作者：
Buttò, S;Fiorelli, V;Ensoli, B
通讯作者：
Ensoli, B
影响因子：
5.1
作者：
Leifert, JA;Harkins, S;Whitton, JL
通讯作者：
Whitton, JL
影响因子：
11.2
作者：
Mishra, Mamara;Vetrivel, S.;Seth, Pankaj
通讯作者：
Seth, Pankaj