Enhanced mucosal immunoglobulin A response of intranasal adenoviral vector human immunodeficiency virus vaccine and localization in the central nervous system
Enhanced mucosal immunoglobulin A response of intranasal adenoviral vector human immunodeficiency virus vaccine and localization in the central nervous system
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DOI：
10.1128/jvi.77.18.10078-10087.2003
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发表时间：
2003-09-01
影响因子：
5.4
通讯作者：
Nabel, GJ
中科院分区：
文献类型：
--
作者：
Lemiale, F;Kong, WP;Nabel, GJ
复制缺陷腺病毒（ADV）载体为艾滋病疫苗的开发提供了一个有希望的潜在平台。虽然这种载体通常是肌肉内给药，但通过其他途径给药诱导粘膜免疫是可取的。本研究对不同途径ADV载体的免疫应答和生物分布进行了评价。将表达人类免疫缺陷病毒1型（HIV-1） Gag、Pol和Env的ADV载体肌内或鼻内送入小鼠体内。鼻内免疫诱导的粘膜分泌物和血清中的hiv特异性免疫球蛋白A （IgA）应答比肌内注射大，显示出更强的全身细胞和IgG应答。通过鼻内途径接种疫苗未能克服先前的ADV免疫。在疫苗接种前暴露于ADV的动物对HIV抗原的细胞和体液免疫反应在两组中均显著降低，尽管鼻内免疫动物的降低幅度更大。在用病毒载体增强之前，用表达HIV-1 Gag、Pol和Env的DNA表达载体引物部分克服了这种抑制。鼻内注射重组腺病毒（rADV）载体的生物分布揭示了中枢神经系统的感染，特别是嗅球，可能通过鼻上皮嗅觉神经元的逆行运输，这可能限制了基于ADV载体的疫苗的这种递送途径的效用。
Replication-defective adenovirus (ADV) vectors represent a promising potential platform for the development of a vaccine for AIDS. Although this vector is typically administered intramuscularly, it would be desirable to induce mucosal immunity by delivery through alternative routes. In this study, the immune response and biodistribution of ADV vectors delivered by different routes were evaluated. ADV vectors expressing human immunodeficiency virus type 1 (HIV-1) Gag, Pol, and Env were delivered intramuscularly or intranasally into mice. Intranasal immunization induced greater HIV-specific immunoglobulin A (IgA) responses in mucosal secretions and sera than in animals with intramuscular injection, which showed stronger systemic cellular and IgG responses. Administration of the vaccine through an intranasal route failed to overcome prior ADV immunity. Animals exposed to ADV prior to vaccination displayed substantially reduced cellular and humoral immune responses to HIV antigens in both groups, though the reduction was greater in animals immunized intranasally. This inhibition was partially overcome by priming with a DNA expression vector expressing HIV-1 Gag, Pol, and Env before boosting with the viral vector. Biodistribution of recombinant adenovirus (rADV) vectors administered intranasally revealed infection of the central nervous system, specifically in the olfactory bulb, possibly via retrograde transport by olfactory neurons in the nasal epithelium, which may limit the utility of this route of delivery of ADV vector-based vaccines.