ROLE OF MONOCYTES IN AIDS AND AS TARGETS FOR ANTIVIRAL THERAPY

单核细胞在艾滋病中的作用及其作为抗病毒治疗的靶标

• 批准号: 6289680
• 负责人: SHARON M WAHL
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6289680
• 关键词: AIDS therapy; HIV infections; Mycobacterium avium; Pneumocystis carinii; antiviral agents; comorbidity; helper T lymphocyte; human immunodeficiency virus 1; human tissue; in situ hybridization; laboratory mouse; macrophage; monocyte; protease inhibitor; saliva; secretory immune system; virus RNA; virus infection mechanism; virus replication

Despite the presence of HIV-1 in the oral cavity, transmission of the virus through saliva is rare, which implicates innate/natural antiviral mechanisms for suppressing transmission. Such endogenous antiviral molecules, including secretory leukocyte protease inhibitor (SLPI) and thrombospondin (TSP-1) inhibit HIV-1 infection of mononuclear cells during or soon after internalization. To further clarify the antiviral functions of SLPI as well as its role in innate host defense, a multifaceted approach has revealed that in addition to antiproteolytic activity, SLPI inhibits the transcription factor NF-kappa B to block monocyte/macrophage cytokine and chemokine synthesis. Generation of mice homozygous for a null mutation of SLPI have provided insight into its patterns of expression, function and regulation. In additional studies focusing on the regulation of HIV production after infection, opportunistic pathogens and immune activation were shown to influence viral replication. For example, Mycobacterium avium promotes HIV infection by activating the NF-kappa B pathway to stimulate cytokine and chemokine production and HIV co-receptor (CCR5) expression, while inhibiting apoptosis. This results in accumulation of susceptible viral host cells which favors viral replication. In tonsils and in sites of mucosal inflammation, the dynamic relationship between lymphocytes, macrophages and high levels of HIV emphasizes that immune activation contributes to viral progression and suggests interventional approaches.

尽管HIV-1存在于口腔中，但通过唾液传播的病毒很少，这意味着先天/天然抗病毒机制可以抑制传播。这种内源性抗病毒分子，包括分泌性白细胞蛋白酶抑制剂（SLPI）和血小板反应蛋白（TSP-1），在内化过程中或内化后不久抑制单核细胞的HIV-1感染。为了进一步阐明SLPI的抗病毒功能以及其在先天宿主防御中的作用，多方面的方法已经揭示，除了抗蛋白水解活性之外，SLPI还抑制转录因子NF-κ B以阻断单核细胞/巨噬细胞细胞因子和趋化因子的合成。产生SLPI无效突变的纯合子小鼠提供了对其表达、功能和调节模式的深入了解。在关注感染后HIV产生的调节的其他研究中，机会致病菌和免疫激活被证明会影响病毒复制。例如，鸟分枝杆菌通过激活NF-κ B途径以刺激细胞因子和趋化因子产生以及HIV共受体（CCR 5）表达，同时抑制细胞凋亡来促进HIV感染。这导致易感病毒宿主细胞的积累，这有利于病毒复制。在扁桃体和粘膜炎症部位，淋巴细胞、巨噬细胞和高水平HIV之间的动态关系强调免疫激活有助于病毒进展，并建议采取干预措施。