Immune Dysfunction in HIV + Opiod Users

HIV阿片使用者的免疫功能障碍

基本信息

批准号：
10845088
负责人：
Savita Pahwa
金额：
$ 38.11万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-15 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10845088
关键词：
ATAC-seq Affect Age Age Distribution Aging Analgesics Antibodies Antibody Formation Antibody Response Antigens B-Lymphocytes Binding Biological Assay CD4 Positive T Lymphocytes Cell Communication Characteristics Chronic Cities Data Databases Dependence Elderly Enrollment Epidemic Exhibits Grant HIV HIV Infections HIV/AIDS Helper-Inducer T-Lymphocyte Hemagglutination Hemagglutinin Immune System Diseases Immune response Immune system Immunity Immunoglobulin G Immunoglobulin M Impairment Incidence Inflammation Inflammatory Inflammatory Response Influenza Hemagglutinin Influenza vaccination Interferons Investigation Morphine Nature Neuraminidase Opioid Outcome Output Participant Pathway interactions Pattern Peripheral Persons Population Recording of previous events Role ST14 gene Signal Induction Signal Pathway Signal Transduction T-Cell Activation T-Lymphocyte Testing Universities Vaccine Antigen Vaccines Western Blotting addiction age effect age group age related aged chronic pain cohort cytokine expectation flu follow-up immune activation influenza virus vaccine injection drug use member memory CD4 T lymphocyte monocyte non-opioid analgesic opioid abuse opioid epidemic opioid use opioid use disorder parent grant recruit response seasonal influenza study population tool transcriptome sequencing vaccine response

项目摘要

Abstract Miami is at the epicenter of the US HIV/AIDS epidemic, leading U.S. cities in HIV incidence with the highest HIV infection case rate (51.2 per 100,000). Concurrently, dependence on or addiction to opioids is widely prevalent, more so in the HIV+ population that is vulnerable for multiple reasons including need for pain medications. The University of Miami is actively pursuing projects to curb HIV and opioid epidemics. We are currently conducting a study to investigate the impact of opioids on immune responses in PWH and PWoH as compared to non- opioid users with and without HIV. The premise for the primary grant (R01DA051202) was that HIV infection and opioids are independently harmful for the immune system. HIV impairs immunity that is associated with persisting immune activation even after durable virologic control, while opioids (OP) are immunosuppressive. Together, they can potentially compound the damage to the immune system, leading us to hypothesize that people with HIV (PWH) who abuse opioids are likely to damage their immune system which would grossly blunt the immune response to influenza vaccine. We enrolled 4 study groups on the basis of HIV status and chronic opioid use: HIV+OP+, HIV+OP-, HIV-OP+, HIV-OP- using stringent enrollment criteria to evaluate flu vaccine induced Ab responses as well as B/T cell interaction by study of peripheral T follicular helper cells (Tfh), the memory CD4 T cells that are intimately involved in stimulating B cells to produce Ab to vaccine antigens. We found that the HIV+OP+ group exhibited high level of inflammation and immune activation (IA). We used rigorous statistical tools, and determined that Opioids were the major drivers of inflammation while HIV was the main driver of cellular immune activation of T cells. Unexpectedly, we found that people with OUD had better Ab responses based on titer and fold increase from baseline than non-opioid using population, and the same was true for HIV+OP+ group in comparison to HIV+OP- group, which had the lowest Ab responses as expected. Age in the study population as a whole was inversely correlated with Ab responses, but we do not have sufficient numbers of aged people with OUD in our cohort to assess if age was influencing the immune response or whether OP also circumvent the deleterious effects of HIV or Aging on Flu vaccine response. In this supplement, we plan to enroll additional “old” OUD participants to assess the impact of age on the immune response and understand whether OP use can circumvent the deleterious effects of Aging or of HIV on Flu vaccine responses. We will investigate if underlying mechanisms involve a unique inflammatory cytokine pattern or signaling pathways in monocytes that affect their cytokine output. We also plan to examine the nature of the Flu Ab secreted to assess whether the secreted Ab has functional diversity.

抽象的迈阿密是美国艾滋病流行的中心，是美国艾滋病发病率最高的城市之一感染病例率（每 100,000 人中有 51.2 人），同时，对阿片类药物的依赖或成瘾也普遍存在。对于因多种原因（包括需要止痛药）而易受感染的艾滋病毒携带者来说更是如此。迈阿密大学正在积极开展遏制艾滋病毒和阿片类药物流行的项目。一项研究调查阿片类药物与非阿片类药物相比对 PWH 和 PWoH 免疫反应的影响患有和不患有艾滋病毒的阿片类药物使用者。主要拨款 (R01DA051202) 的前提是艾滋病毒感染。阿片类药物对免疫系统独立有害，会损害与艾滋病毒相关的免疫力。即使在持久的病毒学控制后，免疫激活仍持续存在，而阿片类药物 (OP) 具有免疫抑制作用。它们一起可能会加剧对免疫系统的损害，从而使我们能够捕捉到这一点滥用阿片类药物的艾滋病毒感染者 (PWH) 可能会损害他们的免疫系统，从而严重削弱他们的免疫系统我们根据艾滋病毒状况和慢性病情况招募了 4 个研究组。阿片类药物使用：HIV+OP+、HIV+OP-、HIV-OP+、HIV-OP- 使用严格的入组标准来评估流感疫苗通过对外周滤泡辅助性 T 细胞 (Tfh) 的研究，诱导抗体反应以及 B/T 细胞相互作用，记忆 CD4 T 细胞与刺激 B 细胞产生疫苗抗原抗体密切相关。我们发现 HIV+OP+ 组表现出高水平的炎症和免疫激活 (IA)。严格的统计工具，并确定阿片类药物是炎症的主要驱动因素，而艾滋病毒是炎症的主要驱动因素出乎意料的是，我们发现 OUD 患者的情况更好。与非阿片类药物使用群体相比，抗体反应基于效价和相对于基线的增加倍数，并且相同与 HIV+OP- 组相比，HIV+OP+ 组的情况如此，后者具有预期的最低抗体反应。整个研究人群的年龄与抗体反应呈负相关，但我们没有足够的证据我们队列中患有 OUD 的老年人数量，以评估年龄是否影响免疫反应或 OP 是否还能避免 HIV 或衰老对流感疫苗反应的有害影响。我们计划招募更多“老”OUD 参与者来评估年龄对免疫反应的影响，了解OP的使用是否可以避免衰老或艾滋病毒对流感疫苗反应的有害影响。我们将研究潜在机制是否涉及独特的炎症细胞因子模式或信号传导我们还计划检查单核细胞中影响其细胞因子输出的途径。分泌以评估分泌的抗体是否具有功能多样性。