ROLE OF EXOGENOUS ACTIVATION OF THE IMMUNE SYSTEM IN THE PATHOGENESIS OF HIV DIS

免疫系统外源激活在 HIV DIS 发病机制中的作用

• 批准号: 6288919
• 负责人: Mario Ostrowski
• 金额: --
• 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/6288919
• 关键词: AIDS; HIV infections; clinical research; helper T lymphocyte; human immunodeficiency virus 1; human subject; human therapy evaluation; human tissue; immunization; leukocyte activation /transformation; leukocyte count; microorganism immunology; monocyte; pathologic process; provirus; receptor expression; serotyping; tetanus toxoid; tissue mosaicism; virus load; AIDS; HIV infections; clinical research; helper T lymphocyte; human immunodeficiency virus 1; human subject; human therapy evaluation; human tissue; immunization; leukocyte activation /transformation; leukocyte count; microorganism immunology; monocyte; pathologic process; provirus; receptor expression; serotyping; tetanus toxoid; tissue mosaicism; virus load

This project involves a number of clinically based studies directed at delineating the pathogenic mechanisms of human immunodeficiency virus (HIV) infection and the role of immune activation in the propagation of disease and destruction of the immune system. We have demonstrated that, after tetanus toxoid booster inoculation, HIV-1 infected patients had transient increases in plasma viremia after immunization, increases in proviral burden, and increased virus within lymph nodes. HIV was more easily isolated from PBMCs from the majority of patients after immunization than before immunization. We also demonstrated an enhanced susceptibility of PBMCs to HIV infection in normal volunteers after tetanus immunization. Phylogenetic analysis of the viral bursts within plasma in most cases reflected a non-specific increase in viral replication, secondary to an expanded pool of susceptible CD4+ T cells. An exception to this was in a patient in which immunization favored the expansion of M-tropic (CCR5 utilizing) over T-tropic(CXCR4-utilizing) viruses. In one of three patients the data suggested that immune activation resulted in the appearance in plasma of virus induced from latently infected cells. A cross-sectional study was performed which evaluated the expression of CCR5 and CXCR4 in whole blood samples taken from 25 HIV-1-infected and 10 uninfected individuals. We found that co- receptor expression correlated with the level of cellular activation in vivo in both HIV-1-infected and uninfected individuals, with CXCR4 being expressed predominantly on quiescent (HLA-DR -)T cells and CCR5 being expressed predominantly on activated (HLA-DR+) T cells. Lower expression of CXCR4 and higher expression of CCR5 on CD4+ T cells correlated with advancing disease. Twenty-three individuals with various forms of acute and chronic filariasis and 10 blood bank controls were studied. We found a modest increase in susceptibility of unstimulated PBMCs taken from filariasis patients in comparison to controls. In 6 patients with filariasis, the susceptibility to infection was evaluated pre- and post-filaria treatment. In three out of six patients, anti-filarial treatment significantly decreased susceptibility to infection, whereas in the other three, it was unchanged. - Immune activation; HIV; viral quasispecies; HIV co- receptor; filariasis - Human Subjects

该项目涉及许多基于临床的研究，该研究涉及描述人类免疫缺陷病毒（HIV）感染的致病机制，以及免疫激活在疾病传播和免疫系统破坏中的作用。我们已经证明，在破伤风毒素促进接种后，HIV-1感染的患者在免疫后血浆病毒血症的瞬时增加，前病毒负担增加并增加了淋巴结内病毒。与免疫之前相比，从大多数患者的PBMC中更容易从大多数患者中分离HIV。我们还证明了破伤风免疫后正常志愿者中PBMC对HIV感染的敏感性增强。在大多数情况下，血浆内病毒爆发的系统发育分析反映了病毒复制的非特异性增加，其次是易感CD4+ T细胞扩大的库。一个例外是，在患者中，免疫有利于Mtropic（CCR5利用）而不是T-热带（CXCR4利用）病毒的病毒。在三名患者中，数据表明免疫激活导致受到潜在感染细胞诱导的病毒的血浆出现。进行了一项横断面研究，该研究评估了从25个受HIV-1感染和10个未感染个体的全血样品中CCR5和CXCR4的表达。我们发现，在HIV-1感染和未感染的个体中，共同体表达与体内细胞活化水平相关，CXCR4主要在静态（HLA-DR-）T细胞（HLA-DR-）T细胞和CCR5上以激活（HLA-DR+）T细胞为主要表达。 CXCR4的较低表达和CCR5在CD4+ T细胞上的较高表达与疾病相关。研究了二十三个患有各种形式的急性和慢性丝虫病以及10个血库控制的人。我们发现，与对照组相比，从丝虫病患者中取出的未刺激的PBMC的敏感性适度增加。在6例丝虫病患者中，对感染的敏感性进行了评估，并在治疗后治疗后进行了评估。在六名患者中，有三名抗抗疗法显着降低了对感染的敏感性，而在其他三例中，它没有变化。 - 免疫激活；艾滋病病毒;病毒式列； HIV共同受体；丝虫病 - 人类受试者