During chronic HIV-1 infection, continuing viral replication is associated with impaired proliferative capacity of virus-specific CD8+ T cells and with the expansion and persistence of oligoclonal T cell populations. TCR usage may significantly influence CD8+ T cell-mediated control of AIDS viruses; however, the potential to modulate the repertoire of functional virus-specific T cells by immunotherapy has not been explored. To investigate this, we analyzed the TCR Vbeta usage of CD8+ T cells populations which were expanded following vaccination with modified vaccinia virus Ankara expressing a HIV-1 gag/multiepitope immunogen (MVA.HIVA) in HIV-1-infected patients receiving highly active antiretroviral therapy. Vaccinations induced the re-expansion of HIV-1-specific CD8+ T cells and these showed broad TCR Vbeta usage which was maintained for at least 1 year in some individuals. By contrast, virus-specific CD8+ T cell populations in the same donors which failed to expand after vaccination and in unvaccinated controls were oligoclonal. Simultaneously, we observed that CD8+ T cells recognizing vaccine-derived HIV-1 epitopes displayed enhanced capacity to proliferate and to inhibit HIV-1 replication in vitro, following MVA.HIVA immunizations. Taken together, these data indicate that an attenuated viral-vectored vaccine can modulate adaptive CD8+ T cell responses to HIV-1 and improve their antiviral functional capacity. The potential therapeutic benefit of this vaccination approach warrants further investigation.

译文

:在慢性HIV-1感染期间,持续的病毒复制与病毒特异性CD8 T细胞的增殖能力受损以及寡克隆T细胞群体的扩张和持续存在有关。 TCR的使用可能会显着影响CD8 T细胞介导的对AIDS病毒的控制;然而,尚未探索通过免疫疗法调节功能性病毒特异性T细胞库的潜力。为了对此进行调查,我们分析了在接受高活性抗逆转录病毒治疗的HIV-1感染患者中,用表达HIV-1 gag /多表位免疫原(MVA.HIVA)的改良牛痘病毒安卡拉疫苗接种后扩大的CD8 T细胞群体的TCR Vbeta使用治疗。疫苗接种可诱导HIV-1特异性CD8 T细胞的再扩增,这些疫苗显示出广泛的TCR Vbeta使用率,在某些人中至少维持了1年。相比之下,相同供体中的病毒特异性CD8 T细胞群体在接种疫苗后未能扩增,而在未接种疫苗的对照组中则是寡克隆的。同时,我们观察到,在MVA.HIVA免疫后,识别疫苗衍生的HIV-1表位的CD8 T细胞在体外具有增强的增殖能力和抑制HIV-1复制的能力。综上所述,这些数据表明减毒的病毒载体疫苗可以调节对HIV-1的适应性CD8 T细胞应答并提高其抗病毒功能能力。这种疫苗接种方法的潜在治疗益处值得进一步研究。

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