Institute of Infectious Disease and Molecular Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America ; Division of Medical Virology, Department of Clinical Laboratory Science, Albert Einstein College of Medicine, Bronx, New York, United States of America.
PLoS One. 2013 Aug 20;8(8):e71601. doi: 10.1371/journal.pone.0071601. eCollection 2013.
In previous studies we have shown that a pantothenate auxotroph of Myocbacterium bovis BCG (BCGΔpanCD) expressing HIV-1 subtype C Gag induced Gag-specific immune responses in mice and Chacma baboons after prime-boost immunization in combination with matched rMVA and VLP vaccines respectively. In this study recombinant BCG (rBCG) expressing HIV-1 subtype C reverse transcriptase and a truncated envelope were constructed using both the wild type BCG Pasteur strain as a vector and the pantothenate auxotroph. Mice were primed with rBCG expressing Gag and RT and boosted with a recombinant MVA, expressing a polyprotein of Gag, RT, Tat and Nef (SAAVI MVA-C). Priming with rBCGΔpanCD expressing Gag or RT rather than the wild type rBCG expressing Gag or RT resulted in higher frequencies of total HIV-specific CD8(+) T cells and increased numbers of T cells specific to the subdominant Gag and RT epitopes. Increasing the dose of rBCG from 10(5) cfu to 10(7) cfu also led to an increase in the frequency of responses to subdominant HIV epitopes. A mix of the individual rBCGΔpanCD vaccines expressing either Gag, RT or the truncated Env primed the immune system for a boost with SAAVI MVA-C and generated five-fold higher numbers of HIV-specific IFN-γ-spot forming cells than mice primed with rBCGΔpanCD containing an empty vector control. Priming with the individual rBCGΔpanCD vaccines or the mix and boosting with SAAVI MVA-C also resulted in the generation of HIV-specific CD4(+) and CD8(+) T cells producing IFN-γ and TNF-α and CD4(+) cells producing IL-2. The rBCG vaccines tested in this study were able to prime the immune system for a boost with rMVA expressing matching antigens, inducing robust, HIV-specific T cell responses to both dominant and subdominant epitopes in the individual proteins when used as individual vaccines or in a mix.
在之前的研究中，我们已经表明，表达 HIV-1 亚型 C Gag 的泛酸钙营养缺陷型分枝杆菌卡介苗（BCGΔpanCD）在分别与匹配的 rMVA 和 VLP 疫苗联合进行初免-加强免疫接种后，可在小鼠和 Chacma 狒狒中诱导 Gag 特异性免疫反应。在这项研究中，我们使用野生型卡介苗 Pasteur 株作为载体构建了表达 HIV-1 亚型 C 逆转录酶和截断包膜的重组卡介苗（rBCG）。用 rBCGΔpanCD 表达 Gag 和 RT 进行初免，用表达 Gag、RT、Tat 和 Nef 多蛋白的重组 MVA（SAAVI MVA-C）进行加强免疫，接种 rBCGΔpanCD 表达 Gag 或 RT 的小鼠比接种野生型 rBCG 表达 Gag 或 RT 的小鼠产生更高频率的总 HIV 特异性 CD8(+)T 细胞，并且增加了针对亚优势 Gag 和 RT 表位的 T 细胞数量。将 rBCG 的剂量从 10(5)cfu 增加到 10(7)cfu 也会导致对亚优势 HIV 表位的反应频率增加。用表达 Gag、RT 或截断的 Env 的单个 rBCGΔpanCD 疫苗混合接种可使免疫系统对 SAAVI MVA-C 加强免疫做出反应，并产生比用含有空载体对照的 rBCGΔpanCD 疫苗接种的小鼠高五倍的 HIV 特异性 IFN-γ 斑点形成细胞。用单个 rBCGΔpanCD 疫苗或混合疫苗初免并用 SAAVI MVA-C 加强免疫还可诱导产生 HIV 特异性 IFN-γ 和 TNF-α 的 CD4(+)和 CD8(+)T 细胞和产生 IL-2 的 CD4(+)细胞。在这项研究中测试的 rBCG 疫苗能够对表达匹配抗原的 rMVA 进行加强免疫，当用作单个疫苗或混合疫苗时，可诱导针对单个蛋白中的优势和亚优势表位的强烈、HIV 特异性 T 细胞反应。
