Priming with DNA Expressing Trimeric HIV V1V2 Alters the Immune Hierarchy Favoring the Development of V2-Specific Antibodies in Rhesus Macaques.
Priming with DNA Expressing Trimeric HIV V1V2 Alters the Immune Hierarchy Favoring the Development of V2-Specific Antibodies in Rhesus Macaques.
复制标题
用表达三聚体HIV V1V2的DNA引发改变免疫层次，有利于恒河猴中V2特异性抗体的发展。
DOI：
10.1128/jvi.01193-20
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发表时间：
2020-12-22
影响因子：
5.4
通讯作者：
Felber BK
中科院分区：
文献类型：
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作者：
Devasundaram S;Rosati M;Valentin A;Weiss S;Itri V;Trinh HV;Bear J;Chowdhury B;LaBranche CC;Montefiori D;Ferrari G;Rao M;Kong XP;Zolla-Pazner S;Pavlakis GN;Felber BK
这项工作的目的是设计和测试一种疫苗方案，将免疫反应集中在与感染预防相关的目标上。我们证明，用只表达HIV Env V1V2区域的DNA疫苗引发针对V2中与保护相关的关键区域的抗体反应。这项工作表明，V1V2支架DNA引物免疫提供了一种在没有其他表位免疫干扰的情况下将免疫反应集中到所需目标区域的方法。在RV144试验中，这诱导了免疫应答，增强了对保护性免疫重要表位的识别，即与HIV感染风险负相关的v2特异性体液免疫应答。RV144疫苗试验揭示了HIV感染风险降低与针对HIV gp120包膜（Env）蛋白第二可变结构域（V2）特异性表位的非中和抗体（Ab）应答水平之间的相关性，表明该区域可作为疫苗开发的靶点。为了促进诱导v2特异性抗体，我们在恒河猴中开发了一种疫苗方案，包括用表达HIV V1V2三聚体支架免疫原的DNA引物，然后用DNA和蛋白质组合加强免疫。与表达CRF01_AE gp145 Env的DNA接种相比，用表达HIV重组亚型CRF01_AE V1V2支架的DNA启动疫苗接种可诱导更高、更广泛的v2特异性抗体反应。识别被报道为RV144关键靶点的V2肽的抗体只有在用V1V2 DNA启动免疫后才能产生。v2特异性抗体显示出几种非中和性fc介导的功能，包括ADCP和C1q结合。重要的是，通过gp145 DNA和gp120蛋白共同免疫，增强了v2特异性抗体。总之，用表达三聚体V1V2支架的DNA引物改变了对V2区表位的体液免疫应答的等级，提供了一种更有效的诱导和维持V2特异性Env抗体的方法，与降低HIV感染风险相关。这项工作的目的是设计和测试一种疫苗方案，将免疫反应集中在与感染预防相关的目标上。我们证明，用只表达HIV Env V1V2区域的DNA疫苗引发针对V2中与保护相关的关键区域的抗体反应。这项工作表明，V1V2支架DNA引物免疫提供了一种在没有其他表位免疫干扰的情况下将免疫反应集中到所需目标区域的方法。在RV144试验中，这诱导了免疫应答，增强了对保护性免疫重要表位的识别，即与HIV感染风险负相关的v2特异性体液免疫应答。
The aim of this work was to design and test a vaccine regimen focusing the immune response on targets associated with infection prevention. We demonstrated that priming with a DNA vaccine expressing only the HIV Env V1V2 region induces Ab responses targeting the critical region in V2 associated with protection. This work shows that V1V2 scaffold DNA priming immunization provides a method to focus immune responses to the desired target region, in the absence of immune interference by other epitopes. This induced immune responses with improved recognition of epitopes important for protective immunity, namely, V2-specific humoral immune responses inversely correlating with HIV risk of infection in the RV144 trial. The RV144 vaccine trial revealed a correlation between reduced risk of HIV infection and the level of nonneutralizing-antibody (Ab) responses targeting specific epitopes in the second variable domain (V2) of the HIV gp120 envelope (Env) protein, suggesting this region as a target for vaccine development. To favor induction of V2-specific Abs, we developed a vaccine regimen that included priming with DNA expressing an HIV V1V2 trimeric scaffold immunogen followed by booster immunizations with a combination of DNA and protein in rhesus macaques. Priming vaccination with DNA expressing the HIV recombinant subtype CRF01_AE V1V2 scaffold induced higher and broader V2-specific Ab responses than vaccination with DNA expressing CRF01_AE gp145 Env. Abs recognizing the V2 peptide that was reported as a critical target in RV144 developed only after the priming immunization with V1V2 DNA. The V2-specific Abs showed several nonneutralizing Fc-mediated functions, including ADCP and C1q binding. Importantly, robust V2-specific Abs were maintained upon boosting with gp145 DNA and gp120 protein coimmunization. In conclusion, priming with DNA expressing the trimeric V1V2 scaffold alters the hierarchy of humoral immune responses to V2 region epitopes, providing a method for more efficient induction and maintenance of V2-specific Env Abs associated with reduced risk of HIV infection. IMPORTANCE The aim of this work was to design and test a vaccine regimen focusing the immune response on targets associated with infection prevention. We demonstrated that priming with a DNA vaccine expressing only the HIV Env V1V2 region induces Ab responses targeting the critical region in V2 associated with protection. This work shows that V1V2 scaffold DNA priming immunization provides a method to focus immune responses to the desired target region, in the absence of immune interference by other epitopes. This induced immune responses with improved recognition of epitopes important for protective immunity, namely, V2-specific humoral immune responses inversely correlating with HIV risk of infection in the RV144 trial.