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.

尽管经过多年联合抗逆转录病毒治疗 (cART) 并抑制 HIV-1 RNA 水平<40 拷贝/mL，HIV-1 前病毒仍持续存在于 HIV 感染者的 CD4+ T 细胞中。在循环外周血单核细胞 (PBMC) 中检测到的这些原病毒中，95% 以上由于具有大量内部缺失和致命的基因突变而被认为是有缺陷的。由于这些有缺陷的原病毒无法编码完整且具有复制能力的病毒，因此长期以来它们被认为是与生物学无关的病毒墓地，对 HIV-1 发病机制意义不大。与这一观点相反，我们最近证明这些有缺陷的原病毒不是沉默的，能够转录具有有效开放阅读框（ORF）的新型未剪接形式的HIV-RNA转录物，并且可以在以下人群的外周血CD4+T细胞中找到： HIV-1感染各个阶段的患者。在没有病毒复制的情况下持续产生 HIV-1 蛋白有助于解释尽管 HIV-1 水平低于检测水平但持续的免疫激活，并且也对根除 HIV-1 提出了新的挑战。 我们观察到，在接受 ART 治疗的患者中，存在多个独特的转录活性“缺陷”HIV-1 原病毒克隆（平均：11 岁，范围：4-20 岁）的长期持续存在以及针对 HIV-1 病毒蛋白的抗体反应参与者。观察到 HIV-1 抗体反应的强度与“缺陷”HIV-1 原病毒的转录水平之间存在直接相关性。还注意到总 CD8 + T 细胞计数与 HIV-DNA 或细胞相关 HIV-RNA 之间存在其他相关性。 这些发现表明，“有缺陷的”HIV-1原病毒的转录和翻译与慢性HIV-1感染治疗过程中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

Decreased Absorption of Dolutegravir and Tenofovir Disoproxil Fumarate, But Not Emtricitabine, in an HIV-Infected Patient Following Oral and Jejunostomy-Tube Administration.

• DOI: 10.1002/phar.1960
• 发表时间: 2017-08
• 期刊: Pharmacotherapy
• 影响因子: 4.1
• 作者: Brooks KM;Garrett KL;Kuriakose SS;George JM;Balba G;Bailey B;Anderson M;Lane HC;Maldarelli F;Pau AK
• 通讯作者: Pau AK

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