HIV Nef Function and Early Events in Macrophage and Microglia Infection

HIV Nef 功能以及巨噬细胞和小胶质细胞感染的早期事件

基本信息

批准号：
7735124
负责人：
Jon W Marsh
金额：
$ 83.85万
依托单位：
NATIONAL INSTITUTE OF MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
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/7735124
关键词：
Acquired Immunodeficiency Syndrome Actins Acute Biochemical Brain CCR5 gene CD4 Positive T Lymphocytes CXCL10 gene CXCR4 Receptors CXCR4 gene Cardiovascular system Cell Nucleus Cell surface Cells DNA Sequence Rearrangement DNA delivery Deterioration Disease Endopeptidases Environment Epidemic Event Evolution Excision Future Genes Goals HIV HIV Infections HIV drug resistance Human IL8 gene Impairment Individual Infection Inflammation Lead Longevity Mediating Microglia Molecular Neurocognitive Pathogenesis Pathogenicity Pathology Patients Peptide Hydrolases Population Process Recruitment Activity Resistance Rest Reverse Transcriptase Inhibitors SIV Signal Transduction T memory cell T-Lymphocyte Tissues Transcript United States Viral Virus brain cell chemokine cofilin macrophage nef Genes nef Protein neutrophil particle receptor response

项目摘要

The objective of this study is to elucidate those early events in HIV infection that may lead to pathogenesis. Two important advances were made this last year. Macrophages are infected in the circulatory system as well as in the brain. We have identified the early innate immunological responses following HIV infection of primary human macrophages: induction of the chemokines CXCL8 and CXCL10. CXCL8 recruits neutrophils, which are the hallmark of acute inflammation and can mediate tissue damage; CXCL10, also generated by the HIV-infected macrophage, recruits activated CD4 T cells and more macrophages, which become productively infected by the macrophage HIV particles. HIV has evolved to use two chemokine co-receptors to infect macrophages, microglia, and T cells. One is CCR5, expressed on macrophages, microglia, and active, memory T cells. HIV readily infects these cells. The other co-receptor, CXCR4, is expressed on quiescent naive CD4 T cells, which are naturally resistant to retroviral infection; however, in AIDS patients the CXCR4-utilizing virus usually shows up late in the disease and commonly coincides with rapid deterioration. We have discovered that the interaction of HIV envelope with cell surface CXCR4 alters the cellular structural components to render these cells susceptible to infection. We have found that the signal from HIV engagement of the CXCR4 co-receptor activates cofilin, which leads to cortical actin rearrangements and HIV DNA delivery to the nucleus. This finding demonstrates an evolved selection of the co-receptor CXCR4 by HIV to alter the cellular biochemical environment so that it is supportive of infection, as well as suggests that defective viral particles, or circulating HIV envelope can in fact prime resting T cells for productive infection. Future efforts will include identifying the mechanism(s) of CXCL8 and CXCL10 induction by HIV infection of macrophages, and how this might contribute to pathogenesis. We will also continue our exploration of the biochemical activity of the Nef protein.

本研究的目的是阐明 HIV 感染中可能导致发病机制的早期事件。去年取得了两项重要进展。巨噬细胞在循环系统和大脑中都被感染。我们已经确定了人类原代巨噬细胞感染 HIV 后的早期先天免疫反应：趋化因子 CXCL8 和 CXCL10 的诱导。 CXCL8 招募中性粒细胞，这是急性炎症的标志，可以介导组织损伤； CXCL10 也是由 HIV 感染的巨噬细胞产生的，它会招募激活的 CD4 T 细胞和更多的巨噬细胞，这些巨噬细胞会被巨噬细胞 HIV 颗粒有效地感染。 HIV 已进化为使用两种趋化因子辅助受体来感染巨噬细胞、小胶质细胞和 T 细胞。其中之一是 CCR5，在巨噬细胞、小胶质细胞和活性记忆 T 细胞上表达。 HIV很容易感染这些细胞。另一个辅助受体 CXCR4 在静止的幼稚 CD4 T 细胞上表达，这些细胞对逆转录病毒感染具有天然抵抗力；然而，在艾滋病患者中，利用 CXCR4 的病毒通常在疾病晚期才出现，并且通常伴随着快速恶化。我们发现 HIV 包膜与细胞表面 CXCR4 的相互作用改变了细胞结构成分，使这些细胞容易受到感染。我们发现，来自 HIV 与 CXCR4 辅助受体结合的信号会激活丝切蛋白，从而导致皮质肌动蛋白重排和 HIV DNA 递送至细胞核。这一发现证明了 HIV 对辅助受体 CXCR4 的进化选择，以改变细胞生化环境，从而支持感染，并表明有缺陷的病毒颗粒或循环的 HIV 包膜实际上可以启动静息 T 细胞的生产能力。感染。未来的工作将包括确定 HIV 感染巨噬细胞诱导 CXCL8 和 CXCL10 的机制，以及这如何促进发病机制。我们还将继续探索Nef蛋白的生化活性。