Immune Dysfunction in HIV + Opiod Users

HIV阿片使用者的免疫功能障碍

• 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
• 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

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.

摘要 迈阿密是美国艾滋病毒/艾滋病流行的中心，是美国艾滋病毒发病率最高的城市 感染率（每10万人51.2例）。与此同时，对类阿片的依赖或成瘾普遍存在， 在艾滋病毒阳性人群中更是如此，他们由于多种原因而脆弱，包括需要止痛药。的 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。我们目前正在进行 研究阿片类药物对PWH和PWO患者免疫反应的影响，与非 阿片类药物使用者，无论是否携带艾滋病毒。主要补助金（R 01 DA 051202）的前提是， 和阿片类药物对免疫系统都是有害的。艾滋病毒会损害免疫力， 即使在持久的病毒学控制后，持续的免疫激活，而阿片类药物（OP）是免疫抑制性的。 它们一起可能会加剧对免疫系统的损害，这使我们假设， 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， 对流感疫苗的免疫反应。我们根据艾滋病毒感染状况和慢性感染情况招募了4个研究组。 阿片类药物用途：HIV+OP+、HIV+OP-、HIV-OP+、HIV-OP-使用严格的入组标准评价流感疫苗 诱导的抗体反应以及B/T细胞相互作用的研究外周T滤泡辅助细胞（Tfh）， 记忆性CD 4 T细胞密切参与刺激B细胞产生针对疫苗抗原的Ab。我们 发现HIV+OP+组表现出高水平的炎症和免疫激活（IA）。我们使用 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。 T细胞的细胞免疫激活的主要驱动力。出乎意料的是，我们发现OUD患者 与非阿片类药物使用人群相比，基于滴度和较基线增加倍数的Ab应答， 与HIV +OP-组相比，HIV+OP+组确实如此，如预期的那样，HIV+OP-组具有最低的Ab应答。 研究人群的年龄总体上与抗体应答呈负相关，但我们没有足够的证据表明， 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应答， OP是否也规避了HIV或衰老对流感疫苗应答的有害影响。在这份补充中， 我们计划招募更多的“老年”OUD参与者，以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HIV对流感疫苗反应的有害影响。 我们将研究潜在的机制是否涉及独特的炎症细胞因子模式或信号传导 影响单核细胞细胞因子输出的信号通路。我们亦计划研究流感抗体的性质， 分泌的抗体以评估分泌的抗体是否具有功能多样性。