Microbiology Doctoral Training Program, University of Wisconsin-Madison, 1326 Microbial Sciences, 1550 Linden Drive, Madison, WI 53706, USA.
Immunogenetics. 2012 Feb;64(2):111-21. doi: 10.1007/s00251-011-0566-0. Epub 2011 Sep 1.
Every year, Dengue virus (DENV) infects approximately 100 million people. There are currently several vaccines undergoing clinical studies, but most target the induction of neutralizing antibodies. Unfortunately, DENV infection can be enhanced by subneutralizing levels of antibodies that bind virions and deliver them to cells of the myeloid lineage, thereby increasing viral replication (termed antibody-dependent enhancement [ADE]). T lymphocyte-based vaccines may offer an alternative that avoids ADE. The goal of our study was to describe the cellular immune response generated after primary DENV infection in Indian rhesus macaques. We infected eight rhesus macaques with 10⁵ plaque-forming units (PFU) of DENV serotype 2 (DENV2) New Guinea C (NGC) strain, and monitored viral load and the cellular immune response to the virus. Viral replication peaked at day 4 post-infection and was resolved by day 10. DENV-specific CD4+ and CD8+ T lymphocytes targeted nonstructural (NS) 1, NS3 and NS5 proteins after resolution of peak viremia. DENV-specific CD4+ cells expressed interferon-gamma (IFN-γ) along with tumor necrosis factor-alpha (TNF-α), interleukin-2 (IL-2), and macrophage inflammatory protein-1 beta (MIP-1β). In comparison, DENV-specific CD8+ cells expressed IFN-γ in addition to MIP-1β and TNF-α and were positive for the degranulation marker CD107a. Interestingly, a fraction of the DENV-specific CD4+ cells also stained for CD107a, suggesting that they might be cytotoxic. Our results provide a more complete understanding of the cellular immune response during DENV infection in rhesus macaques and contribute to the development of rhesus macaques as an animal model for DENV vaccine and pathogenicity studies.
每年，登革病毒（DENV）感染约 1 亿人。目前有几种疫苗正在进行临床研究，但大多数都针对诱导中和抗体。不幸的是，DENV 感染可以通过结合病毒粒子并将其递送至髓系细胞的亚中和水平的抗体增强（称为抗体依赖性增强[ADE]）。基于 T 淋巴细胞的疫苗可能提供一种避免 ADE 的替代方法。我们的研究目标是描述印度恒河猴初次 DENV 感染后产生的细胞免疫反应。我们用 10⁵ 噬菌斑形成单位（PFU）的 DENV 血清型 2（DENV2）新几内亚 C（NGC）株感染了 8 只恒河猴，并监测病毒载量和对病毒的细胞免疫反应。病毒复制在感染后第 4 天达到峰值，并在第 10 天消退。在峰值病毒血症消退后，DENV 特异性 CD4+和 CD8+T 淋巴细胞针对非结构（NS）1、NS3 和 NS5 蛋白。DENV 特异性 CD4+细胞表达干扰素-γ（IFN-γ）以及肿瘤坏死因子-α（TNF-α）、白细胞介素-2（IL-2）和巨噬细胞炎症蛋白-1β（MIP-1β）。相比之下，DENV 特异性 CD8+细胞除了 MIP-1β和 TNF-α外还表达 IFN-γ，并且对脱颗粒标记物 CD107a 呈阳性。有趣的是，一部分 DENV 特异性 CD4+细胞也对 CD107a 染色，这表明它们可能具有细胞毒性。我们的结果提供了对恒河猴 DENV 感染期间细胞免疫反应的更全面理解，并有助于开发恒河猴作为 DENV 疫苗和致病性研究的动物模型。
