一种新型候选 HIV 疫苗载体，基于复制缺陷的 Capripoxvirus，即羊痘病毒（LSDV）。
A novel candidate HIV vaccine vector based on the replication deficient Capripoxvirus, Lumpy skin disease virus (LSDV).
机构信息
Institute of Infectious Disease and Molecular Medicine, UCT, Cape Town, South Africa.
出版信息
Virol J. 2011 May 30;8:265. doi: 10.1186/1743-422X-8-265.
BACKGROUND
The Capripoxvirus, Lumpy skin disease virus (LSDV) has a restricted host-range and is being investigated as a novel HIV-1 vaccine vector. LSDV does not complete its replication cycle in non-ruminant hosts.
METHODS
The safety of LSDV was tested at doses of 104 and 106 plaque forming units in two strains of immunocompromised mice, namely RAG mice and CD4 T cell knockout mice. LSDV expressing HIV-1 subtype C Gag, reverse transcriptase (RT), Tat and Nef as a polyprotein (Grttn), (rLSDV-grttn), was constructed. The immunogenicity of rLSDV-grttn was tested in homologous prime-boost regimens as well as heterologous prime-boost regimes in combination with a DNA vaccine (pVRC-grttn) or modified vaccinia Ankara vaccine (rMVA-grttn) both expressing Grttn.
RESULTS
Safety was demonstrated in two strains of immunocompromised mice.In the immunogenicity experiments mice developed high magnitudes of HIV-specific cells producing IFN-gamma and IL-2. A comparison of rLSDV-grttn and rMVA-grttn to boost a DNA vaccine (pVRC-grttn) indicated a DNA prime and rLSDV-grttn boost induced a 2 fold (p < 0.01) lower cumulative frequency of Gag- and RT-specific IFN-γ CD8 and CD4 cells than a boost with rMVA-grttn. However, the HIV-specific cells induced by the DNA vaccine prime rLSDV-grttn boost produced greater than 3 fold (p < 0.01) more IFN- gamma than the HIV-specific cells induced by the DNA vaccine prime rMVA-grttn boost. A boost of HIV-specific CD4 cells producing IL-2 was only achieved with the DNA vaccine prime and rLSDV-grttn boost. Heterologous prime-boost combinations of rLSDV-grttn and rMVA-grttn induced similar cumulative frequencies of IFN- gamma producing Gag- and RT-specific CD8 and CD4 cells. A significant difference (p < 0.01) between the regimens was the higher capacity (2.1 fold) of Gag-and RT-specific CD4 cells to produce IFN-γ with a rMVA-grttn prime - rLSDV-grttn boost. This regimen also induced a 1.5 fold higher (p < 0.05) frequency of Gag- and RT-specific CD4 cells producing IL-2.
CONCLUSIONS
LSDV was demonstrated to be non-pathogenic in immunocompromised mice. The rLSDV-grttn vaccine was immunogenic in mice particularly in prime-boost regimens. The data suggests that this novel vaccine may be useful for enhancing, in particular, HIV-specific CD4 IFN- gamma and IL-2 responses induced by a priming vaccine.
背景
羊痘病毒（Lumpy skin disease virus，LSDV）宿主范围有限，目前正被研究作为一种新型 HIV-1 疫苗载体。LSDV 无法在非反刍动物宿主中完成其复制周期。
方法
在两种免疫功能低下的小鼠模型，即 RAG 小鼠和 CD4 T 细胞敲除小鼠中，以 104 和 106 噬斑形成单位的剂量测试 LSDV 的安全性。构建了表达 HIV-1 亚型 C Gag、逆转录酶（RT）、Tat 和 Nef 作为多蛋白（Grttn）的 LSDV（rLSDV-grttn）。在同源初免-加强免疫方案以及与 DNA 疫苗（pVRC-grttn）或改良安卡拉痘苗（rMVA-grttn）联合使用的异源初免-加强免疫方案中，测试了 rLSDV-grttn 的免疫原性，这两种疫苗均表达 Grttn。
结果
在两种免疫功能低下的小鼠模型中，安全性得到了证明。在免疫原性实验中，小鼠产生了大量产生 IFN-γ 和 IL-2 的 HIV 特异性细胞。与 rMVA-grttn 相比，rLSDV-grttn 和 rMVA-grttn 加强 DNA 疫苗（pVRC-grttn）的效果表明，DNA 初免和 rLSDV-grttn 加强诱导的 Gag 和 RT 特异性 IFN-γ CD8 和 CD4 细胞累积频率低 2 倍（p < 0.01）。然而，由 DNA 疫苗初免 rLSDV-grttn 加强诱导的 HIV 特异性细胞产生的 IFN-γ 多于由 DNA 疫苗初免 rMVA-grttn 加强诱导的 HIV 特异性细胞产生的 IFN-γ，倍数大于 3（p < 0.01）。只有在 DNA 疫苗初免和 rLSDV-grttn 加强时才能诱导产生产生 IL-2 的 HIV 特异性 CD4 细胞。rLSDV-grttn 和 rMVA-grttn 的异源初免-加强组合诱导产生的 Gag 和 RT 特异性 IFN-γ 产生的 CD8 和 CD4 细胞累积频率相似。方案之间存在显著差异（p < 0.01），即 rMVA-grttn 初免-rLSDV-grttn 加强方案诱导的 Gag 和 RT 特异性 CD4 细胞产生 IFN-γ 的能力更高（2.1 倍）。该方案还诱导产生 Gag 和 RT 特异性 CD4 细胞产生 IL-2 的频率提高 1.5 倍（p < 0.05）。
结论
在免疫功能低下的小鼠中，LSDV 被证明无致病性。rLSDV-grttn 疫苗在小鼠中具有免疫原性，特别是在初免-加强免疫方案中。数据表明，这种新型疫苗可能有助于增强由初免疫苗诱导的 HIV 特异性 CD4 IFN-γ 和 IL-2 反应。
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