Integrated neuroimmune model of problematic substance use and depression in people living with HIV

项目总结 尽管艾滋病毒的治疗取得了重大进展，但艾滋病毒携带者(PLWH)面临着更大的负担 与未感染艾滋病毒的人相比，患有多种与老龄化相关的慢性病。物质使用，抑郁，和 全身性炎症是与衰老相关的慢性疾病的危险因素，在 PLWH。需要研究来确定驱动物质使用、抑郁和全身炎症的因素 在青壮年的PLWH中，在慢性病预防仍然可行的年龄段。大脑的中枢 执行网络(CEN)在实施自我控制、重新评估应激刺激和管理方面起着关键作用 侵扰性的想法。这些技能对于在面对压力的生活中管理负面情绪至关重要 情况。因此，较低的CEN功能可能会增加与应激相关的心理健康结果的易感性， 例如抑郁症和药物使用。在艾滋病毒携带者中，更多的药物使用和抑郁 可能会减少对抗逆转录病毒治疗(ART)的依从性。减少对ART的坚持可能会导致更大的系统性 发炎。更严重的全身炎症可能导致CEN功能下降。依次降低CEN功能， 可能会进一步增加对问题物质使用和抑郁的易感性。因此，公共卫生署可能会在 陷入抑郁症状增加、药物使用增加、ART降低的恶性循环的风险 粘附性，增加全身炎症，降低CEN功能。该项目将测试一个集成的 青壮年HIV感染者样本中问题物质使用和抑郁的神经免疫模型 (n=246)参加了对出生时被指定为男性的性和性别少数族裔青年进行的一项队列研究 (例如，男同性恋者和双性恋者、跨性别女性、非双性恋者)。该项目具有相当大的临床应用价值。 之所以重要是因为之前的研究表明，CEN功能可以通过干预得到改善 比如认知训练、冥想和神经调节。因此，改善CEN功能可能会证明 成为艾滋病毒护理计划的重要新组成部分，旨在减少药物使用，改善精神健康， 最大限度地提高抗逆转录病毒治疗的依从性，并减少PLWH的全身炎症。为了制作这个新奇的项目 在可行的情况下，申请者组建了一支拥有神经科学、临床心理学、 以及HIV的发病机制。申请者的主要职业目标是建立一个独立资助的研究 物质使用、心理健康和慢性衰老相关疾病的神经免疫学方案 艾滋病毒携带者(PLWH)为此，申请者将接受高级培训和研究 与他的职业目标相关的三个相互关联的研究领域的经验：(1)有问题的物质使用 在PLWH中，(2)脑连通性的神经影像，(3)PLWH的慢性炎症。这个项目将 还提供机会和正规培训，以进一步发展他的手稿写作技能， 开发和项目管理。熟练掌握这些关键技能和研究领域将 使申请者具备成为艾滋病毒研究领域独立资助的研究员的能力。

PROJECT SUMMARY Despite major advances in the treatment of HIV, people living with HIV (PLWH) experience greater burdens of multiple aging-related chronic diseases compared to people without HIV. Substance use, depression, and systemic inflammation are risk factors for aging-related chronic diseases and occur at higher rates among PLWH. Research is needed to identify factors that drive substance use, depression, and systemic inflammation among PLWH in young adulthood, at ages when chronic disease prevention is still feasible. The brain’s central executive network (CEN) plays a key role in exerting self-control, reappraising stressful stimuli, and managing intrusive thoughts. These skills are critical for managing negative emotions when facing stressful life circumstances. Lower CEN function may thus increase susceptibility to stress-related mental health outcomes, such as depression and substance use. Among people living with HIV, greater substance use and depression may reduce adherence to antiretroviral therapy (ART). Reduced ART adherence may lead to greater systemic inflammation. Greater systemic inflammation may lead to lower CEN function. Lower CEN function, in turn, may further increase susceptibility to problematic substance use and depression. PLWH may therefore be at risk of falling into a vicious cycle of increased depressive symptoms, increased substance use, lower ART adherence, increased systemic inflammation, and reduced CEN function. This project will test an integrated neuroimmune model of problematic substance use and depression in a sample of young adults living with HIV (n=246) who are enrolled in RADAR, a cohort study of sexual and gender minority youth assigned male at birth (e.g., gay and bisexual men, trans women, non-binary individuals). This project has considerable clinical importance because previous research suggests that CEN function can be improved through interventions such as cognitive training, meditation, and neuromodulation. Improving CEN function may therefore prove to be an important new component of HIV care plans aimed at reducing substance use, improving mental health, maximizing ART adherence, and reducing systemic inflammation among PLWH. To make this novel project feasible, the applicant has assembled a team of mentors with expertise in neuroscience, clinical psychology, and HIV pathogenesis. The applicant’s primary career goal is to establish an independently funded research program on the neuroimmunology of substance use, mental health, and chronic aging-related diseases among people living with HIV (PLWH). To this end, the applicant will receive advanced training and research experience in three interrelated research domains relevant to his career goals: (1) Problematic substance use among PLWH, (2) Neuroimaging of brain connectivity, and (3) Chronic inflammation in PLWH. This project will also provide opportunities and formal training to further develop his skills in manuscript writing, grant development, and project management. Building proficiency in these key skills and research domains will equip the applicant to become an independently funded investigator in HIV research.