Investigating the effect of oral microbiome on cognition in HIV-infected chronic cannabis users

项目摘要 在人类免疫缺陷病毒(艾滋病毒)感染的背景下，大麻使用是一个重要的主题，是 艾滋病毒感染者最常使用的药物。大麻使用的积极和消极影响 艾滋病毒的背景已经被报道与各种生物过程有关，包括认知能力和免疫 功能。从大麻增强认知功能到导致认知能力协同下降，各种报道不一而足。 因此，在免疫紊乱下，长期使用大麻对艾滋病毒认知的确切作用和限度仍然存在。 不清楚。本研究的目的是研究与大麻相关的口腔微生物群对健康的影响。 关注临床(目标1)和临床前(目标2)神经艾滋病毒在HIV疾病中的神经认知表现 模特们。我们和其他同事已经发现放线菌物种细菌(如A.meyeri和A. 在人类口腔中，与长期吸食大麻的人的唾液相比， 与未感染的人相比，非使用者和A.meyeri在艾滋病毒感染的人中更加丰富。但口述A。 在吸烟者或长期吸食可卡因的人中，物种丰富并不明显。此外，口服液的丰富 A.meyeri的发病与首次使用大麻的年龄较小有关。在这里，我们的目标是调查A.物种 细菌在HIV神经发病机制中起着重要作用。为实现这一目标，在具体目标1中，艾滋病毒大麻 将对使用者进行评估，以确定与大麻使用相关的口腔微生物群之间的联系(即，浓缩 通过关注1)唾液细菌群、真菌菌群和血浆 A.种细菌抗原的移位；2)A.种细菌介导TLR2的分子机制 髓系细胞中信号通路的激活；3)神经认知能力及其与微生物组的关系。 特殊目的2将利用两个成熟的神经艾滋病毒转基因(TG)小鼠模型，包括 HIV TG26 TG和HIV TAT TG小鼠，使我们能够确定：1)接触THC和CBD的慢性影响 对神经认知和神经病理的影响；2)THC和CBD暴露对A. 抗逆转录病毒(ART)药物对脑的细菌和髓系细胞渗透的种类；以及3)机制 与大麻相关的阿米耶里细菌对神经认知、神经病理学和内源性大麻素水平的影响。 了解慢性吸食大麻对口腔微生物群的影响及其对神经认知的影响 在HIV疾病中的表现是决定其在患者治疗中的治疗效果和限度的关键 在传统联合抗逆转录病毒治疗下加速中枢神经系统的发病 (购物车)。

Project Summary In the context of human immunodeficiency virus (HIV) infection, cannabis use is an important topic and is the most commonly used drug among HIV-infected individuals. Positive and negative effects of cannabis use in the context of HIV have been reported for various biological processes, including cognitive performance and immune function. Reports vary from cannabis enhancing cognitive function to causing synergistic decline in cognition. Thus, the exact role and limits of chronic cannabis use on HIV cognition under immune perturbations remain unclear. The aim of the present study is to investigate the effects of cannabis-associated oral microbiome on neurocognitive performance in HIV disease by focusing on clinical (Aim 1) and preclinical (Aim 2) neuroHIV models. We and other colleagues have found that Actinomyces species bacteria (e.g. A. meyeri and A. odontolyticus) in the oral cavity of humans, are enriched in the saliva from chronic cannabis users compared to non-users and A. meyeri is enriched in HIV-infected individuals compared to uninfected individuals. But oral A. species enrichment was not demonstrable in tabacco smokers or chronic cocaine users. Further, oral enrichment of A. meyeri was associated with younger age of first cannabis use. Here, we aim to investigate if A. species bacteria has a significant role in HIV neuropathogenesis. To achieve this goal, in Specific Aim 1, HIV cannabis users will be assessed to determine the link between cannabis use-associated oral microbiome (i.e., enrichment of A. meyeri) and cognitive performance by focusing on 1) saliva bacteriome and mycobiome and plasma translocation of A. species bacterial antigens; 2) molecular mechanisms of A. species bacteria mediated TLR2 signaling pathway activation in myeloid cells; 3) neurocognitive performance and its association with microbiome. Specific Aim 2 will make use of two well-established transgenic (tg) mouse models of neuroHIV, including the HIV Tg26 tg and the HIV Tat tg mice, to allow us to determine: 1) the chronic effects of THC and CBD exposure on neurocognition and neuropathology; 2) the chronic effects of THC and CBD exposure on enrichment of A. species bacteria and myeloid cell infiltration to the brain under antiretroviral (ART) drugs; and 3) the mechanisms of cannabis-associated A. meyeri bacteria on neurocognition, neuropathology, and endocannabinoid levels. Understanding the role of chronic cannabis use on oral microbiome and it’s effects on neurocognitive performance in HIV disease is critical to determine its therapeutic benefits and limits in the treatment of patients with accelerated central nervous system pathogenesis under traditional combination antiretroviral therapy (cART).