Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA.
Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA.
J Virol. 2020 Dec 22;95(2). doi: 10.1128/JVI.01193-20.
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. 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.
RV144 疫苗试验揭示了 HIV 感染风险降低与针对 HIV gp120 包膜 (Env) 蛋白第二可变区 (V2) 中特定表位的非中和抗体 (Ab) 反应水平之间的相关性，表明该区域是疫苗开发的目标。为了有利于诱导 V2 特异性 Abs，我们开发了一种疫苗方案，该方案包括用表达 HIV V1V2 三聚体支架免疫原的 DNA 进行初免，然后用 DNA 和蛋白质的组合在恒河猴中进行加强免疫。用表达 HIV 重组亚型 CRF01_AE V1V2 支架的 DNA 进行初免接种可诱导更高和更广泛的 V2 特异性 Ab 反应，优于用表达 CRF01_AE gp145 Env 的 DNA 进行接种。只有在用 V1V2 DNA 进行初免免疫后，才能检测到识别 RV144 报告的关键靶标 V2 肽的 Abs。V2 特异性 Abs 表现出几种非中和 Fc 介导的功能，包括 ADCP 和 C1q 结合。重要的是，在用 gp145 DNA 和 gp120 蛋白共免疫加强免疫后，仍能维持强大的 V2 特异性 Abs。总之，用表达三聚体 V1V2 支架的 DNA 进行初免可改变针对 V2 区域表位的体液免疫反应的层次结构，为更有效地诱导和维持与 HIV 感染风险降低相关的 V2 特异性 Env Abs 提供了一种方法。本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预防感染相关的靶点上。我们证明，用仅表达 HIV Env V1V2 区域的 DNA 疫苗进行初免可诱导针对与保护相关的 V2 中关键区域的 Ab 反应。这项工作表明，V1V2 支架 DNA 初免免疫接种提供了一种将免疫反应集中在所需目标区域的方法，而不会受到其他表位的免疫干扰。这诱导了免疫反应，提高了对保护性免疫重要表位的识别，即与 RV144 试验中 HIV 感染风险呈负相关的 V2 特异性体液免疫反应。
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