Pathogenesis and Treatment of HIV Infection

HIV感染的发病机制和治疗

• 批准号: 10927743
• 负责人: H. Clifford Lane
• 金额: $ 94.01万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10927743
• 关键词: Acquired Immunodeficiency Syndrome; Anti-Retroviral Agents; Antibody Response; Bar Codes; Binding; Blood; CD4 Antigens; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Count; Cell Survival; Cells; Chronic; Coagulation Process; DNA; DNA Sequence Alteration; Detection; Environment; Genetic Transcription; Genome; HIV; HIV Infections; HIV-1; Homeostasis; Immune system; Immunologic Deficiency Syndromes; Immunologic Stimulation; Immunosuppression; Individual; Infection; Inflammation; Knowledge; Ligands; Measurement; Measures; Open Reading Frames; Participant; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Positron-Emission Tomography; Production; Proteins; Proviruses; RNA; RNA Viruses; Resistance; Risk; Secondary to; Transcript; Translations; Viral Proteins; Viremia; Virus; Virus Replication; antiretroviral therapy; immune activation; immunological status; innovation; novel; patient population; peripheral blood; treatment strategy

HIV-1 proviruses persist in the CD4+ T cells of HIV-infected individuals despite years of combination antiretroviral therapy (cART) with suppression of HIV-1 RNA levels <40 copies/mL. Greater than 95% of these proviruses detected in circulating peripheral blood mononuclear cells (PBMCs) are referred to as defective by virtue of having large internal deletions and lethal genetic mutations. As these defective proviruses are unable to encode intact and replication-competent viruses, they have long been thought of as biologically irrelevant graveyard of viruses with little significance to HIV-1 pathogenesis. Contrary to this notion, we have recently demonstrated that these defective proviruses are not silent, are capable of transcribing novel unspliced forms of HIV-RNA transcripts with competent open reading frames (ORFs), and can be found in the peripheral blood CD4+ T cells of patients at all stages of HIV-1 infection. The persistent production of HIV-1 proteins in the absence of viral replication helps explain persistent immune activation despite HIV-1 levels below detection, and also presents new challenges to HIV-1 eradication. We observed long-term persistence of multiple, unique, transcriptionally-active "defective" HIV-1 provirus clones (average: 11 yrs., range: 4-20 yrs.) and antibody responses against HIV-1 viral proteins among ART-treated participants. A direct correlation was observed between the magnitude of HIV-1 antibody response and the levels of transcription of "defective" HIV-1 proviruses. Additional correlations were noted between total CD8 + T cell counts and HIV-DNA or cell associated HIV-RNA. These findings suggest a novel interplay between transcription and translation of "defective" HIV-1 proviruses and the persistent immune activation seen in the setting of treated chronic HIV-1 infection.

尽管多年的抗逆转录病毒疗法（CART）抑制HIV-1 RNA水平<40拷贝/mL，但HIV-1病毒仍在HIV感染个体的CD4+ T细胞中持续存在。在循环的外周血单核细胞（PBMC）中检测到的这些病毒中的95％以上被称为有缺陷，因为它具有较大的内部缺失和致命的遗传突变。由于这些缺陷的原病毒无法编码完整和复制能力的病毒，因此长期以来，它们被认为是生物学上无关的病毒墓地，对HIV-1发病机理没有意义。与这一概念相反，我们最近证明，这些有缺陷的病毒并不静音，能够用具有胜任的开放式阅读框（ORF）转录新型的无膜状形式的HIV-RNA转录物，并且可以在HIV-1感染的所有阶段的外周血CD4+ T细胞中找到。在缺乏病毒复制的情况下，HIV-1蛋白的持续产生有助于解释尽管HIV-1水平低于检测，但仍为消除HIV-1带来新的挑战。 我们观察到多个，独特的，独特的，具有转录活性的“有缺陷的” HIV-1 Provirus克隆（平均：11年：范围：4-20年）和对ART验证的参与者中HIV-1病毒蛋白的抗体反应的长期持久性。在HIV-1抗体反应的大小与“有缺陷” HIV-1 Proviruse的转录水平之间观察到了直接相关。总CD8 + T细胞计数与HIV-DNA或相关的HIV-RNA之间的其他相关性。 这些发现表明，在处理后的慢性HIV-1感染环境中，“有缺陷” HIV-1病毒的转录与翻译之间的新相互作用与持续的免疫激活之间存在新的相互作用。

项目成果

The role of cytokines in the pathogenesis and treatment of HIV infection.

• DOI: 10.1016/j.cytogfr.2012.05.007
• 发表时间: 2012-08
• 期刊: CYTOKINE & GROWTH FACTOR REVIEWS
• 影响因子: 13
• 作者: Catalfamo, Marta;Le Saout, Cecile;Lane, H. Clifford
• 通讯作者: Lane, H. Clifford

2021 update to HIV-TRePS: a highly flexible and accurate system for the prediction of treatment response from incomplete baseline information in different healthcare settings.

HIV-TRePS 2021 年更新：一个高度灵活且准确的系统，用于根据不同医疗保健环境中不完整的基线信息预测治疗反应。

• DOI: 10.1093/jac/dkab078
• 发表时间: 2021
• 期刊: The Journal of antimicrobial chemotherapy
• 作者: Revell,AndrewD;Wang,Dechao;Perez-Elias,Maria-Jesus;Wood,Robin;Cogill,Dolphina;Tempelman,Hugo;Hamers,RaphL;Reiss,Peter;vanSighem,Ard;Rehm,CatherineA;Agan,Brian;Alvarez-Uria,Gerardo;Montaner,JulioSG;Lane,HClifford;Larder,
• 通讯作者: Larder,

HIV-1 Treated Patients with Undetectable Viral Loads have Lower Levels of Innate Immune Responses via Cytosolic DNA Sensing Systems Compared with Healthy Uninfected Controls.

与未感染的健康对照组相比，接受 HIV-1 治疗且病毒载量无法检测到的患者通过胞质 DNA 传感系统产生的先天免疫反应水平较低。

• DOI: 10.4172/2155-6113.1000315
• 发表时间: 2014
• 期刊: Journal of AIDS & clinical research
• 作者: Swaminathan,Sanjay;Sui,Hongyan;Adelsberger,JosephW;Chen,Qian;Sneller,Michael;Migueles,StephenA;Kottilil,Shyamasundaran;Ober,Alexander;Jones,Sara;Rehm,CatherineA;Lane,HClifford;Imamichi,Tomozumi
• 通讯作者: Imamichi,Tomozumi

Elevations in D-dimer and C-reactive protein are associated with the development of osteonecrosis of the hip in HIV-infected adults.

• DOI: 10.1097/qad.0b013e32835c206a
• 发表时间: 2013-02-20
• 期刊: AIDS (London, England)
• 作者: Morse CG;Dodd LE;Nghiem K;Costello R;Csako G;Lane HC;Lozier JN;Kovacs JA
• 通讯作者: Kovacs JA

The CD8+ HLA-DR+ T cells expanded in HIV-1 infection are qualitatively identical to those from healthy controls.

• DOI: 10.1002/eji.201142046
• 发表时间: 2012-10
• 期刊: EUROPEAN JOURNAL OF IMMUNOLOGY
• 影响因子: 5.4
• 作者: Imamichi, Hiromi;Lempicki, Richard A.;Adelsberger, Joseph W.;Hasley, Rebecca B.;Rosenberg, Alice;Roby, Gregg;Rehm, Catherine A.;Nelson, Amy;Krishnan, Sonya;Pavlick, Mark;Woods, Christian J.;Baseler, Michael W.;Lane, H. Clifford
• 通讯作者: Lane, H. Clifford