Impact of Treatment on Brain Integrity in the Earliest Stages of HIV Infection

HIV 感染早期阶段治疗对大脑完整性的影响

• 批准号: 10201435
• 负责人: Robert H Paul
• 金额: $ 58.73万
• 依托单位: UNIVERSITY OF MISSOURI-ST. LOUIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-25 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201435
• 关键词: Acute; Address; Adjuvant; Age; Astrocytes; Atrophic; Awareness; Biological; Brain; Brain Injuries; Brain region; Cerebrospinal Fluid; Chronic; Clinical; Cognitive; Data; Diagnosis; Diffusion Magnetic Resonance Imaging; Disease; Enrollment; Evolution; Exhibits; Functional Magnetic Resonance Imaging; Funding; HIV; HIV Infections; Health Services Accessibility; Impairment; Individual; Infection; Injury; Institutes; Intervention; Investigation; Link; Literature; Longitudinal Studies; Macrophage Activation; Modeling; Multimodal Imaging; Neopterin; Neurological outcome; Neuronal Dysfunction; Neuropathogenesis; Outcome; Participant; Patient-Focused Outcomes; Patients; Peripheral; Phenotype; Plasma; Positioning Attribute; Recommendation; Reporting; Research; Research Personnel; Resources; Rest; Severities; Structure; Thailand; Time; Viral; Viral Load result; Viral reservoir; Viremia; Work; acute infection; antiretroviral therapy; base; brain abnormalities; cognitive performance; cohort; comparison group; cost; data acquisition; design; expectation; gray matter; improved; migration; model design; monocyte; multimodality; nerve injury; neuroimaging; persistent symptom; prevent; putamen; receptor; recruit; substance use; white matter

ABSTRACT This study addresses a critical gap in the field of HIV neuropathogenesis. Previous investigations of brain integrity during the earliest stages of infection describe two opposing neuroimaging signatures of disease. The inconsistency likely reflects the challenges inherent in conducting this work in the US given the limited access to treatment-naïve individuals in early disease stages (Fiebig I-V). Leveraging a highly unique cohort of acutely infected individuals (AHI) in Thailand, our preliminary data reveals intact brain structure and function in treatment- naïve individuals infected for less than two weeks. However, after two years of suppressive combination antiretroviral therapy (cART) initiated within weeks of infection, neuroimaging abnormalities develop in the context of suppressive cART. Further, the degree of brain impairment corresponds to increased levels of monocytes expressing receptors involved in CNS migration and CSF levels of neuronal dysfunction. In this study we will answer the critical question of whether cART is sufficient to halt the detrimental impact of HIV on the brain when initiated within weeks of infection, or whether the brain abnormalities observed in our preliminary analyses progress beyond expectations for HIV- controls despite otherwise successful treatment. This study will overcome limitations in the existing literature because all participants in this study will start cART within days of viral exposure. This work is timely and builds on funded studies that will substantially leverage costs of data acquisition. We will examine longitudinal multimodal imaging outcomes (resting state fMRI, diffusion tensor imaging, and structural volumetrics) of AHI (n=60) as well as enrollment and data capture from demographically-similar individuals with chronic HIV infection (CHI; n=40) and HIV- controls (n=40). A mixed model design will determine if individuals with AHI develop brain injury similar to CHI despite suppressive cART and identify key mechanistic predictors to the evolution of brain abnormalities. Confirmation of our preliminary data demonstrating progressive brain abnormalities despite initiation of cART during the earliest possible period of infection would provide a strong argument that treatment administered under ideal clinical circumstances does not prevent the onset of brain abnormalities. Additionally, evidence of persistent neural injury despite cART instituted during AHI would identify key mechanisms of HIV neuropathogenesis and potential high-impact targets for clinical interventions.

摘要 这项研究解决了HIV神经发病机制领域的一个关键空白。以前对大脑完整性的研究 在感染的最早阶段，描述了两种相反的疾病神经影像学特征。的 不一致性可能反映了在美国开展这项工作所固有的挑战， 疾病早期阶段的初治个体（Fiebig I-V）。利用一个高度独特的急性 在泰国的AHI感染者中，我们的初步数据显示，治疗过程中大脑结构和功能完好无损， 未感染的人感染时间不到两周。然而，经过两年的压制组合， 在感染后数周内开始抗逆转录病毒治疗（cART）， 抑制性CART此外，脑损伤的程度对应于单核细胞水平的增加， 表达参与CNS迁移的受体和神经元功能障碍的CSF水平。在这项研究中，我们将 回答cART是否足以阻止艾滋病毒对大脑的有害影响的关键问题， 在感染后数周内开始，或者在我们的初步分析中观察到的大脑异常是否进展 尽管其他方面的治疗是成功的，但在艾滋病毒控制方面超出了预期。这项研究将克服局限性 因为本研究中的所有参与者都将在病毒暴露后的几天内开始cART。这项工作 是及时的，并建立在资助的研究，将大大利用数据采集成本。我们将研究 纵向多模态成像结果（静息状态fMRI、弥散张量成像和结构体积测量） AHI（n=60）以及从人口统计学相似的慢性HIV患者中招募和采集数据 感染组（CHI; n=40）和HIV对照组（n=40）。混合模型设计将确定是否患有AHI的个体发展 尽管抑制性cART，但脑损伤与CHI相似，并确定了 大脑异常证实了我们的初步数据显示，尽管 在尽可能早的感染期开始cART将提供一个强有力的论据， 在理想的临床环境下施用的药物不能防止脑异常的发作。此外，本发明还 尽管在AHI期间实施了cART，但持续性神经损伤的证据将确定HIV的关键机制 神经发病机制和临床干预的潜在高影响目标。

项目成果

Neuropsychiatric and Laboratory Outcomes of Hepatitis C Treatment in an Early-Treated HIV Cohort in Thailand.

泰国早期治疗的艾滋病毒队列中丙型肝炎治疗的神经精神和实验室结果。

• DOI: 10.21203/rs.3.rs-4186965/v1
• 发表时间: 2024
• 期刊: Research square
• 作者: Ocampo,FerronF;Sacdalan,Carlo;Pinyakorn,Suteeraporn;Paudel,Misti;Wansom,Tanyaporn;Poltubtim,Nathornsorn;Sriplienchan,Somchai;Phanuphak,Nittaya;Paul,Robert;Hsu,Denise;Colby,Donn;Trautmann,Lydie;Spudich,Serena;Chan,Phillip
• 通讯作者: Chan,Phillip

Immunological, Cognitive, and Psychiatric Outcomes After Initiating Efavirenz- and Dolutegravir-based Antiretroviral Therapy During Acute Human Immunodeficiency Virus Infection.

• DOI: 10.1093/cid/ciac466
• 发表时间: 2023-02-08
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

Structural and functional brain imaging in acute HIV.

• DOI: 10.1016/j.nicl.2018.07.024
• 发表时间: 2018
• 期刊: NeuroImage. Clinical
• 作者: Samboju V;Philippi CL;Chan P;Cobigo Y;Fletcher JLK;Robb M;Hellmuth J;Benjapornpong K;Dumrongpisutikul N;Pothisri M;Paul R;Ananworanich J;Spudich S;Valcour V;SEARCH 010/RV254;RV304 protocol teams
• 通讯作者: RV304 protocol teams

Individual Differences in CD4/CD8 T-Cell Ratio Trajectories and Associated Risk Profiles Modeled From Acute HIV Infection.

• DOI: 10.1097/psy.0000000000001129
• 发表时间: 2022-10-01
• 期刊: Psychosomatic medicine
• 影响因子: 3.3
• 作者: Paul R;Cho K;Bolzenius J;Sacdalan C;Ndhlovu LC;Trautmann L;Krebs S;Tipsuk S;Crowell TA;Suttichom D;Colby DJ;Premeaux TA;Phanuphak N;Chan P;Kroon E;Vasan S;Hsu D;Carrico A;Valcour V;Ananworanich J;Robb ML;Ake JA;Sriplienchan S;Spudich S;RV254/SEARCH 010 Study Team
• 通讯作者: RV254/SEARCH 010 Study Team