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

描述(申请人提供)：人类免疫缺陷病毒1型(HIV)和结核分枝杆菌(Mtb)是全球主要的死亡原因，合并感染与死亡率增加和选择Mtb多重耐药性的可能性更大有关。在存在艾滋病毒/艾滋病的情况下，结核分枝杆菌的治疗由于与艾滋病毒感染相关的免疫抑制以及用于治疗这两种病原体的药物之间的药理相互作用而变得复杂。需要新的治疗方法，能够抑制结核分枝杆菌，允许在没有复杂的药物-药物相互作用的情况下治疗艾滋病毒，并且在发展中国家负担得起。MTB是一种细胞内病原体，通过干扰巨噬细胞吞噬小体的生物发生而持续存在于巨噬细胞吞噬小体内。越来越多的证据表明，自噬的诱导促进了含有Mtb的吞噬小体的成熟，Mtb抑制了分枝杆菌的生存。最近，我们发现HIV感染巨噬细胞，类似于结核分枝杆菌，抑制自噬，而诱导自噬则抑制HIV的复制。值得注意的是，我们的初步数据表明，骨化三醇是维生素D3的活性形式，长期以来一直与抗结核分枝杆菌的活性有关，它还促进自噬和抗菌素，这两种物质都能抑制艾滋病毒感染。这种R21的应用是基于这样一个前提，即在艾滋病毒和结核分枝杆菌混合感染者中，维生素D3诱导自噬和盲肠毒素将增加对这两种感染的标准治疗，并改善结果。本建议的具体目的是：1.建立维生素D3(骨化三醇)在混合感染的单核细胞来源的巨噬细胞中提高结核杆菌杀伤力和抑制HIV感染的能力；2.确定维生素D3介导的抑制混合感染巨噬细胞中结核分枝杆菌和艾滋病病毒的机制(S)。拟议的实验室实验将为骨化三醇的临床研究奠定科学依据，该研究旨在治疗同时感染这两种病原体的人。此外，这项研究还将证明增强先天免疫对控制微生物感染的潜在益处，包括结核分枝杆菌/艾滋病毒混合感染。公共卫生相关性：7.预计这项赠款中概述的研究将确立骨化三醇(维生素D3的活性形式)诱导自噬的能力，以及足以促进对艾滋病毒和结核分枝杆菌的细胞内杀灭的抗菌肽长春花素。

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.