HIV-1 Specific Immune Responses in Thai Individuals with HIV Dementia

泰国 HIV 痴呆症患者的 HIV-1 特异性免疫反应

• 批准号: 8111296
• 负责人: SILVIA R KIM
• 金额: $ 32.27万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111296
• 关键词: AIDS Dementia Complex; Acquired Immunodeficiency Syndrome; Age; Anti-Retroviral Agents; Antigens; Appearance; Appointment; Area; Autologous; Biological Assay; Brain; CCR5 gene; CD14 gene; CD4 Positive T Lymphocytes; CD8B1 gene; CX3CL1 gene; Cell Count; Cell Line; Cell physiology; Cells; Clinical; Clinical Research; Cytolysis; DNA; Data; Dementia; Development; Diagnosis; Education; Enrollment; Escape Mutant; Evolution; Exposure to; FCGR3B gene; Far East; Gender; Guidelines; HIV; HIV-1; HLA-DR Antigens; Hawaii; Health Planning; Helper-Inducer T-Lymphocyte; Hepatitis C; Illicit Drugs; Immune response; Individual; Infection; Infiltration; Interferons; Investigation; Level of Evidence; Light; Link; Lymphocyte; Macrophage Activation; Measures; Memory; Monitor; Neurologic; Neuropathogenesis; Outcome; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Phenotype; Plasma; Population; Production; Proteins; Public Health; Recruitment Activity; Regimen; Relative (related person); Research Personnel; Resources; Role; SELL gene; Symptoms; T cell response; T-Lymphocyte; Testing; Thailand; Universities; Viral; Virus; Virus Diseases; Work; cohort; cytokine; immune function; innovation; insight; macrophage; member; monocyte; neuropsychological; novel; programs; response; white matter

DESCRIPTION (provided by applicant): The Hawaii AIDS Clinical Research Program (HACRP) has established a cohort of HIV-1 -infected individuals in Bangkok, Thailand to elucidate the mechanisms that induce HIV-1 associated dementia (HAD) in anti-retroviral naive individuals. This application will particularly focus on the role of cellular immune responses in the development of HAD using an expanded cohort of newly enrolled individuals and the established resources. This application is timely because The Thai Ministry of Public Health plans to provide anti-retroviral treatment for all HI V-1-infected individuals according to WHO guidelines. Thus, the opportunity to observe and study HAD before and after anti-retroviral therapy (ARV) within the same individual makes this cohort unique and invaluable. Moreover in contrast to most HIV-1 cohorts established in the US, the enrolled group will comprise of individuals with little to no exposure to illicit drugs, no hepatitis C exposure, and all starting the same ARVs. Therefore, fewer confounding factors exist to impact the HAD diagnosis. Increasing evidence links strong CD4+ T helper function with robust CD8+ CTL responses. HIV-1 - infected individuals who are able to maintain strong HIV-1 specific T cell responses have better clinical outcomes and rarely develop neurological symptoms. Monocyte/macrophage (M/M) infiltration into the white matter of the brain is a hallmark of HAD; yet the mechanisms by which these M/M are recruited to the brain are not clearly understood. We hypothesize that the loss of specific HIV-1 T cell responses results in activation/dysregulation of M/M leading to their accumulation in the brain. The mechanisms pertinent to this loss include: 1) the appearance of viral escape mutants that are no longer recognized by the T cells and 2) the loss of HIV specific CD4+ T cells by viral infection and cytolysis, both of which could results in increased blood M/M activation and infection and the development of HAD. To test this hypothesis we propose to enroll 20 HAD, 20 non-HAD, and 20 seronegative controls to be followed prospectively with neuropsychological data to: 1) define CD4+ and CDS T cell functions specifically by studying HIV-1 specific responses in HAD versus non-HAD individuals; 2) correlate these responses simultaneously with M/M subpopulation cell number, percentage and immune function; 3) correlate these responses with HIV-1 proviral load; and autologous viral sequences (viral escape sequences and HIV quasispecies) 4) correlate the impact of ARV on dementia with changes in immunological responses. The work described in this project will provide new insights into HIV-1 neuropathogenesis and its relationship to peripheral immune responses, thus opening exciting new areas for further investigation. The setting of this study in South East Asia will also provide novel information on how immunological responses correlate with HIV associated dementia in a population that is just starting anti retroviral drugs and is infected with clade E virus.

描述（由申请人提供）：夏威夷艾滋病临床研究计划（HACRP）已在泰国曼谷建立了一组HIV-1感染的个体，以阐明在抗逆转录病毒幼稚个体中诱导HIV-1相关的痴呆症（HAT）的机制。该应用将特别关注细胞免疫反应在使用扩大的新招募的个人和既定资源的发展中的作用。此申请之所以及时，是因为泰国公共卫生部计划根据WHO指南为所有HI V-1感染者提供抗逆转录病毒治疗。因此，观察和研究的机会在同一人群中抗逆转录病毒疗法（ARV）之前和之后有机会使该队列具有独特性和无价之宝。此外，与在美国建立的大多数HIV-1队列相比，入学群体将组成几乎没有非法药物的人，没有乙型肝炎的暴露，并且所有人都开始了相同的ARV。因此，影响诊断的混杂因素较少。越来越多的证据将强CD4+ T辅助功能与鲁棒CD8+ CTL响应联系起来。 HIV-1 - 能够维持强大HIV-1特异性T细胞反应的感染个体具有更好的临床结果，并且很少出现神经系统症状。单核细胞/巨噬细胞（M/M）浸润到大脑的白质中是HAD的标志；然而，尚不清楚将这些M/M招募到大脑的机制。我们假设特定的HIV-1 T细胞反应的丧失导致M/M的激活/失调导致它们在大脑中的积累。与此损失有关的机制包括：1）不再被T细胞识别的病毒逃生突变体的出现，2）通过病毒感染和胞溶液丧失了HIV特异性CD4+ T细胞的丧失，这两者都可能导致血液M/M激活和感染以及HAT的发育增加。为了检验这一假设，我们建议将20个，20个非HAD和20种血清固定控制纳入前瞻性遵循的神经心理学数据，以：1）通过研究HIV-1特异性反应的特定反应与非HAD个体相比，定义了CD4+和CDS T细胞功能； 2）将这些反应同时与M/M亚群的细胞数，百分比和免疫功能相关联； 3）将这些反应与HIV-1前病毒负载相关联；和自体病毒序列（病毒逃生序列和HIV准植物）4）将ARV对痴呆的影响与免疫反应的变化相关联。该项目中描述的工作将为HIV-1神经病发生及其与周围免疫反应的关系提供新的见解，从而为进一步研究开辟了令人兴奋的新领域。这项研究在东南亚的这项研究还将提供有关免疫反应与刚开始抗逆转录病毒药物并感染进化枝E病毒的人群中免疫反应与HIV相关痴呆相关的新信息。

项目成果

Association between brain volumes and HAND in cART-naïve HIV+ individuals from Thailand.

• DOI: 10.1007/s13365-014-0309-8
• 发表时间: 2015-04
• 期刊: JOURNAL OF NEUROVIROLOGY
• 影响因子: 3.2
• 作者: Heaps, Jodi M.;Sithinamsuwan, Pasiri;Paul, Robert;Lerdlum, Sukalaya;Pothisri, Mantana;Clifford, David;Tipsuk, Somporn;Catella, Stephanie;Busovaca, Edgar;Fletcher, James L. K.;Raudabaugh, Benjamin;Ratto-Kim, Silvia;Valcour, Victor;Ananworanich, Jintanat
• 通讯作者: Ananworanich, Jintanat

Brief Report: CD14+ Enriched Peripheral Cells Secrete Cytokines Unique to HIV-Associated Neurocognitive Disorders.

• DOI: 10.1097/qai.0000000000001259
• 发表时间: 2017-04-01
• 期刊: Journal of acquired immune deficiency syndromes (1999)
• 作者: Agsalda-Garcia MA;Sithinamsuwan P;Valcour VG;Chalermchai T;Tipsuk S;Kuroda J;Nakamura C;Ananworanich J;Zhang G;Schuetz A;Slike BM;Shiramizu B;SEARCH 011 Study Group
• 通讯作者: SEARCH 011 Study Group

Change in brain magnetic resonance spectroscopy after treatment during acute HIV infection.

• DOI: 10.1371/journal.pone.0049272
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Sailasuta N;Ross W;Ananworanich J;Chalermchai T;DeGruttola V;Lerdlum S;Pothisri M;Busovaca E;Ratto-Kim S;Jagodzinski L;Spudich S;Michael N;Kim JH;Valcour V;RV254/SEARCH 010 protocol teams
• 通讯作者: RV254/SEARCH 010 protocol teams

Trail Making Test A improves performance characteristics of the International HIV Dementia Scale to identify symptomatic HAND.

• DOI: 10.1007/s13365-013-0151-4
• 发表时间: 2013-04
• 期刊: JOURNAL OF NEUROVIROLOGY
• 影响因子: 3.2
• 作者: Chalermchai, Thep;Valcour, Victor;Sithinamsuwan, Pasiri;Pinyakorn, Suteeraporn;Clifford, David;Paul, Robert H.;Tipsuk, Somporn;Fletcher, James L. K.;DeGruttola, Victor;Ratto-Kim, Silvia;Hutchings, Nicholas;Shikuma, Cecilia;Ananworanich, Jintanat
• 通讯作者: Ananworanich, Jintanat

Characterization of Cellular Immune Responses in Thai Individuals With and Without HIV-Associated Neurocognitive Disorders.

患有和不患有艾滋病毒相关神经认知障碍的泰国人细胞免疫反应的特征。

• DOI: 10.1089/aid.2017.0237
• 发表时间: 2018
• 期刊: AIDS research and human retroviruses
• 影响因子: 1.5
• 作者: Ratto-Kim,Silvia;Schuetz,Alexandra;Sithinamsuwan,Pasiri;Barber,John;Hutchings,Nicholas;Lerdlum,Sukalaya;Fletcher,JamesLK;Phuang-Ngern,Yuwadee;Chuenarom,Weerawan;Tipsuk,Somporn;Pothisri,Mantana;Jadwattanakul,Tanate;Jirajariyavej,
• 通讯作者: Jirajariyavej,