Vitamin D Inhibition of HIV and M. Tuberculosis Coinfection in Macrophages

描述（由申请方提供）：人类免疫缺陷病毒1型（HIV）和结核分枝杆菌（Mtb）是全球主要死因之一，合并感染与死亡率增加和Mtb多重耐药选择的可能性增加相关。在HIV/AIDS存在下Mtb的治疗由于与HIV感染相关的免疫抑制和用于治疗两种病原体的药物之间的药理学相互作用而变得复杂。需要新的治疗方法，这些方法能够抑制结核分枝杆菌，允许治疗艾滋病毒，而不需要复杂的药物相互作用，并且在发展中国家负担得起。结核分枝杆菌是一种细胞内病原体，通过干扰吞噬溶酶体的生物发生而在巨噬细胞吞噬体内持续存在。越来越多的证据表明，诱导自噬促进成熟的吞噬体含有结核分枝杆菌，抑制分枝杆菌的生存。最近，我们发现HIV感染巨噬细胞，类似于Mtb，抑制自噬，而诱导自噬抑制HIV复制。值得注意的是，我们的初步数据表明，骨化三醇，维生素D3的活性形式，长期与可能的抗结核病活性相关，也促进自噬和抗菌肽cathelicidin，两者都抑制HIV感染。这种R21应用是基于这样的前提，即在HIV和Mtb合并感染的人中，维生素D3诱导自噬和cathelicidin将增强这两种感染的标准治疗并改善结果。这项建议的具体目标是：1.建立维生素D3（骨化三醇）在共感染的单核细胞衍生的巨噬细胞（MDM）中提高Mtb杀伤和抑制HIV感染的能力;和2.确定维生素D3介导的Mtb和HIV在共感染巨噬细胞中的抑制机制。所提出的实验室实验将确立骨化三醇临床研究的科学依据，该临床研究旨在治疗合并感染两种病原体的患者。此外，这项研究将证明增强先天免疫力对控制包括结核分枝杆菌/艾滋病毒合并感染在内的微生物感染的潜在益处。公共卫生相关性：7。预计这项资助中概述的研究将确定骨化三醇（维生素D3的活性形式）诱导自噬的能力和抗菌肽凯萨林菌素足以促进HIV和结核分枝杆菌的细胞内杀伤。

DESCRIPTION (provided by applicant): Human Immunodeficiency Virus type-1 (HIV) and Mycobacterium tuberculosis (Mtb) are among the leading causes of death worldwide with coinfection associated with increased mortality and greater likelihood of selection for Mtb multi-drug resistance. Treatment of Mtb in the presence of HIV/AIDS is complicated by the immunosuppression associated with HIV infection and the pharmacologic interactions between drugs used for treatment of both pathogens. New approaches for treatment are needed that can inhibit Mtb, permit treatment of HIV without complex drug-drug interactions and are affordable in developing countries. Mtb is an intracellular pathogen that persists within macrophage phagosomes through interference with phagolysosome biogenesis. Increasing evidence suggests that the induction of autophagy promotes the maturation of phagosomes containing Mtb that suppress mycobacterial survival. Recently, we have discovered that HIV infection of macrophages, similar to Mtb, inhibits autophagy, while induction of autophagy inhibits HIV replication. Of note, our preliminary data suggest that calcitriol the active form of vitamin D3, long associated with possible activity against Mtb, also promotes autophagy and the antimicrobial peptide cathelicidin both of which inhibit HIV infection. This R21 application is based on the premise that induction of autophagy and cathelicidin by vitamin D3 in persons coinfected with HIV and Mtb will augment standard treatment of both infections and improve outcome. The specific aims of this proposal are to: 1. Establish the ability of vitamin D3 (calcitriol) to improve Mtb killing and inhibit HIV infection in coinfected monocyte-derived-macrophages (MDM)); and 2. Identify the mechanism(s) of vitamin D3 mediated inhibition of Mtb and HIV in coinfected macrophages. The laboratory experiments proposed will establish the scientific justification for a clinical study of calcitriol designed to treat persons coinfected with both pathogens. Additionally, this research will demonstrate the potential benefit of enhancing innate immunity to control microbial infections including Mtb/HIV coinfection. PUBLIC HEALTH RELEVANCE: 7. It is expected that the studies outlined in this grant will establish the ability of calcitriol (the active form of vitamin D3) to induce autophagy and the antimicrobial peptide cathelicidin sufficiently to promote intracellular killing of HIV and Mycobacterium tuberculosis.