Hocknell Peter K, Wiley Rebecca D, Wang Xiuqing, Evans Thomas G, Bowers William J, Hanke Tomas, Federoff Howard J, Dewhurst Stephen
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York 14642, USA.
J Virol. 2002 Jun;76(11):5565-80. doi: 10.1128/jvi.76.11.5565-5580.2002.
Herpes simplex virus type 1 (HSV-1) infects a wide range of cells, including dendritic cells. Consequently, HSV-1 vectors may be capable of eliciting strong immune responses to vectored antigens. To test this hypothesis, an HSV-1 amplicon plasmid encoding human immunodeficiency virus type 1 gp120 was constructed, and murine immune responses to helper virus-free amplicon preparations derived from this construct were evaluated. Initial studies revealed that a single intramuscular (i.m.) injection of 10(6) infectious units (i.u.) of HSV:gp120 amplicon particles (HSV:gp120) elicited Env-specific cellular and humoral immune responses. A potent, CD8(+)-T-cell-mediated response to an H-2D(d)-restricted peptide from gp120 (RGPGRAFVTI) was measured by a gamma interferon ELISPOT and was confirmed by standard cytotoxic-T-lymphocyte assays. Immunoglobulin G enzyme-linked immunosorbent assay analysis showed the induction of a strong, Env-specific antibody response. An i.m. or an intradermal administration of HSV:gp120 at the tail base elicited a more potent cellular immune response than did an intraperitoneal (i.p.) inoculation, although an i.p. introduction generated a stronger humoral response. The immune response to HSV:gp120 was durable, with robust cellular and humoral responses persisting at 171 days after a single 10(6)-i.u. inoculation. The immune response to HSV:gp120 was also found to be dose dependent: as few as 10(4) i.u. elicited a strong T-cell response. Finally, HSV:gp120 elicited significant Env-specific cellular immune responses even in animals that had been previously infected with wild-type HSV-1. Taken together, these data strongly support the use of helper-free HSV-1 amplicon particles as vaccine delivery vectors.
1型单纯疱疹病毒（HSV-1）可感染包括树突状细胞在内的多种细胞。因此，HSV-1载体可能能够引发针对载体抗原的强烈免疫反应。为了验证这一假设，构建了一种编码1型人类免疫缺陷病毒gp120的HSV-1扩增子质粒，并评估了小鼠对源自该构建体的无辅助病毒扩增子制剂的免疫反应。初步研究表明，单次肌内注射10⁶感染单位（i.u.）的HSV:gp120扩增子颗粒（HSV:gp120）可引发Env特异性细胞免疫和体液免疫反应。通过γ干扰素ELISPOT检测到对gp120的H-2D(d)限制性肽（RGPGRAFVTI）有强烈的CD8⁺T细胞介导的反应，并通过标准细胞毒性T淋巴细胞试验得到证实。免疫球蛋白G酶联免疫吸附试验分析显示诱导了强烈的Env特异性抗体反应。在尾基部进行HSV:gp120的肌内或皮内给药比腹腔内接种引发更强烈的细胞免疫反应，尽管腹腔内接种产生更强的体液反应。对HSV:gp120的免疫反应具有持久性，在单次接种10⁶i.u.后171天仍存在强烈的细胞免疫和体液免疫反应。还发现对HSV:gp120的免疫反应具有剂量依赖性：低至10⁴i.u.即可引发强烈的T细胞反应。最后，即使在先前感染过野生型HSV-1的动物中，HSV:gp120也能引发显著的Env特异性细胞免疫反应。综上所述，这些数据有力地支持了使用无辅助的HSV-1扩增子颗粒作为疫苗递送载体。
