McGettigan James P, Koser Martin L, McKenna Philip M, Smith Mary Ellen, Marvin Julie M, Eisenlohr Laurence C, Dietzschold Bernhard, Schnell Matthias J
Department of Microbiology and Immunology, Jefferson Medical College, Thomas Jefferson University, 233 South 10th Street, BLSB 330, Philadelphia, PA 19107-6799, USA.
Virology. 2006 Jan 20;344(2):363-77. doi: 10.1016/j.virol.2005.09.004. Epub 2005 Oct 14.
Recombinant rabies virus (RV) vaccine strain-based vectors expressing HIV-1 antigens have been shown to induce strong and long-lasting cellular but modest humoral responses against the expressed antigens in mice. However, an effective vaccine against HIV-1 may require stronger responses, and the development of such an immune response may depend on the presence of certain cytokines at the time of the inoculation. Here, we describe several new RV-based vaccine vehicles expressing HIV-1 Gag or envelope (Env) and murine IL-2 or IL-4. Cells infected with recombinant RVs expressed high levels of functional IL-2 or IL-4 in culture supernatants in addition to HIV-1 proteins. The recombinant RV expressing IL-4 was highly attenuated in a cytokine-independent manner, indicating that the insertion of two foreign genes into the RV genome is mainly responsible for the attenuation observed. The expression of IL-4 resulted in a decrease in the cellular immune response against HIV-1 Gag and Env when compared with the parental virus not expressing IL-4 and only 2 of 20 mice seroconverted to HIV-1 Env after two inoculations. The IL-2-expressing RV was completely apathogenic after direct intracranial inoculation of mice. In addition, mice immunized with IL-2 maintained strong anti-HIV-1 Gag and Env cellular responses and consistently induced seroconversion against HIV-1 Env after two inoculations. This suggests the potential use of IL-2 in RV-based HIV-1 vaccine strategies, which may require the induction of both arms of the immune response.
基于重组狂犬病病毒（RV）疫苗株的载体表达HIV-1抗原，已被证明在小鼠中能诱导针对所表达抗原的强烈且持久的细胞免疫反应，但体液免疫反应较弱。然而，一种有效的抗HIV-1疫苗可能需要更强的免疫反应，而这种免疫反应的发展可能取决于接种时某些细胞因子的存在。在此，我们描述了几种新的基于RV的疫苗载体，它们表达HIV-1的Gag或包膜（Env）以及小鼠白细胞介素-2（IL-2）或白细胞介素-4（IL-4）。除了HIV-1蛋白外，感染重组RV的细胞在培养上清液中还表达高水平的功能性IL-2或IL-4。表达IL-4的重组RV以细胞因子非依赖的方式高度减毒，这表明将两个外源基因插入RV基因组是观察到的减毒的主要原因。与不表达IL-4的亲本病毒相比，IL-4的表达导致针对HIV-1 Gag和Env的细胞免疫反应降低，并且在两次接种后，20只小鼠中只有2只血清转化为HIV-1 Env。直接对小鼠进行颅内接种后，表达IL-2的RV完全无致病性。此外，用IL-2免疫的小鼠保持了强烈的抗HIV-1 Gag和Env细胞免疫反应，并在两次接种后持续诱导血清转化为HIV-1 Env。这表明IL-2在基于RV的HIV-1疫苗策略中具有潜在用途，该策略可能需要诱导免疫反应的两个分支。
