CCR5 and CXCR4 tropism and CD4 kinetics in HIV-1 infection

HIV-1 感染中的 CCR5 和 CXCR4 趋向性以及 CD4 动力学

• 批准号: G0500628/1
• 负责人: Derek Macallan
• 金额: $ 33.68万
• 依托单位: St George's, University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0500628%2F1
• 关键词: CCR5; CXCR4; tropism; CD4; kinetics

HIV infection causes disease by progressively depleting the number of a particular type of immune cells, ?CD4 cells?. We do not fully understand how infection results in loss of CD4 cells over time. Although HIV infects and destroys CD4 cells directly, the body normally just makes more cells to replace the lost ones. We believe that what determines how HIV affects the body?s CD4 cells is the exact type of cell it infects. There are several sub-types of CD4 cells. Different strains of virus prefer to infect different sub-types of CD4 cell according to the receptors (like locking devices) on the cell surface. Two receptors, ?CCR5? and ?CXCR4?, appear particularly important. We hypothesise that the interaction between the viral CCR5/CXCR4 preference (?tropism?), the type of cell infected and the speed at which those cells are dividing determines the long-term effect of HIV on CD4 cell numbers. To investigate this concept, we will measure how fast different sub-types of CD4 cells are dividing and disappearing within the body. Although much has been learnt from investigating cells and viruses in test tubes, answering such questions about CD4 loss can only be done by studying virus and CD4 cells within the body of people infected with HIV. We have recently developed a way of doing this using glucose containing an excess of deuterium. Deuterium is a naturally-occurring non-radioactive form (or isotope) of hydrogen which behaves exactly like hydrogen but can be measured using a mass spectrometer. We will give deuterium-labelled glucose (which is harmless) as a drink (half-hourly for 10 hours) to people with HIV infection, then take blood samples over the following 3 weeks. The glucose is used by dividing, but not non-dividing, cells to make new DNA. By separating the cells into their subtypes and measuring the deuterium in their DNA using a mass spectrometer, we can measure how fast CD4 subtypes divide and how long they survive in the body. We will also test the virus in the bloodstream for its CCR5/CXCR4 tropism. We will compare the results to those from a group of people without HIV infection. We will use these measurements to create a mathematical picture or ?model? of how HIV interacts with different immune cells to explain why CD4 cells are destroyed slowly over time and why changes in viral tropism trigger accelerated loss of CD4 cells.

HIV感染通过逐渐耗尽一种特定类型的免疫细胞--CD4细胞--的数量而导致疾病。随着时间的推移，感染是如何导致CD4细胞丧失的，我们还不完全清楚。虽然HIV直接感染和破坏CD4细胞，但人体通常只是制造更多的细胞来取代丢失的细胞。我们认为，是什么决定了艾滋病毒如何影响人体？S的CD4细胞就是它感染的细胞的确切类型。有几种亚型的CD4细胞。不同的病毒株根据细胞表面的受体(如锁定装置)，倾向于感染不同亚型的CD4细胞。两种受体，CCR5？和CXCR4？，显得尤为重要。我们假设，病毒CCR5/CXCR4偏好(嗜性)、感染细胞的类型和这些细胞分裂的速度之间的相互作用决定了HIV对CD4细胞数量的长期影响。为了研究这一概念，我们将测量不同亚型的CD4细胞在体内分裂和消失的速度。尽管已经从研究试管中的细胞和病毒中学到了很多东西，但回答这些关于CD4丢失的问题只能通过研究HIV感染者体内的病毒和CD4细胞来完成。我们最近开发了一种方法，使用含有过量氢的葡萄糖来实现这一点。氢是一种自然产生的非放射性形式(或同位素)的氢，其行为与氢完全相同，但可以用质谱仪进行测量。我们将给感染艾滋病毒的人服用标记为氘的葡萄糖(无害)作为饮料(每半小时一次，持续10小时)，然后在接下来的三周内采集血样。葡萄糖是通过分裂而不是非分裂的细胞来制造新的DNA。通过将细胞分成不同的亚型，并使用质谱仪测量它们DNA中的氚含量，我们可以测量CD4亚型分裂的速度以及它们在体内存活的时间。我们还将测试血液中的病毒CCR5/CXCR4的趋向性。我们将把结果与一组未感染艾滋病毒的人的结果进行比较。我们将使用这些测量来创建一幅数学图片或模型？研究艾滋病毒如何与不同的免疫细胞相互作用，以解释为什么随着时间的推移，CD4细胞被缓慢破坏，以及为什么病毒嗜性的变化会引发CD4细胞的加速丧失。