Pathogenesis of CCR5-restricted HIV-1

人类免疫缺陷病毒1型(HIV-1)导致艾滋病，迄今已感染澳大利亚约2万人和全球4000多万人。感染艾滋病毒-1的人首先经历5-7年的健康时期，通常在使用抗艾滋病毒-1药物的帮助下保持健康，这段时期被称为无症状期。在此之后，感染者由于免疫系统被破坏而生病，这被称为艾滋病。对HIV-1如何导致艾滋病的研究表明，病毒会随着时间的推移而改变，使自己能够更好地杀死免疫系统的细胞，至少通过两种机制。第一种机制，也是最具特色的一种，是病毒改变感染细胞的方式，通过利用细胞上一种名为CXCR4的替代受体分子，它可以感染体内更多的细胞。这种分子在免疫细胞上广泛表达，因此病毒现在可以感染和杀死更多的细胞。然而，在约50%最终感染艾滋病的感染者中，病毒不会以这种方式发生变化。相反，该病毒使用其原始的受体感染细胞，称为CCR5。我们的初步研究以及其他已发表的报告表明，该病毒通过另一种方式改变自身，使其在不使用CXCR4的情况下更好地杀死免疫细胞。然而，HIV-1病毒做到这一点的机制却知之甚少。这项建议旨在更好地理解这一机制。我们希望发现，在这组患者中，病毒表面的包膜蛋白能够更紧密地结合CCR5，从而能够使用更少的CCR5分子感染细胞。我们认为，这些形式的病毒现在能够更好地杀死免疫细胞，导致艾滋病。这项研究将有助于更好地了解艾滋病毒-1如何导致艾滋病，这对于开发治疗艾滋病毒-1感染的新药是必要的。

Human immunodeficiency virus type 1 (HIV-1) causes AIDS and, to date, has infected approximately 20 thousand people in Australia and more than 40 million worldwide. People infected with HIV-1 first experience a period of 5-7 years where they remain healthy, ofter assisted by the use of anti-HIV-1 drugs, and this period is referred to as the asymptomatic period. After this period, infected individuals become sick due to their immune system being destroyed, and this is referred to as AIDS. Research into how HIV-1 causes AIDS has shown us that the virus changes over time to make itself better able to kill cells of the immune system, by at least 2 mechanisms. The first mechanism, which is the best characterised one, is where the virus changes the way it infects cells, whereby it can infect many more cells in the body by taking advantage of an alternate receptor molecule on the cell called CXCR4. This molecule is very widely expressed on immune cells, and thus the virus can now infect and kill many more cells. However, in about 50% of infected people who eventually get AIDS, the virus does not change this way. The virus instead uses it's original receptor to infect cells, called CCR5. Our preliminary studies, as well as other published reports, suggest that the virus changes itself another way to make it kill immune cells better, without using CXCR4. However, the mechanism by which HIV-1 does this is poorly understood. This proposal aims to better understand this mechanism. We expect to find that, in this group of patients, the Env proteins on the virus change to be able to bind CCR5 more tightly, and thus be able to use fewer molecules of CCR5 to infect cells. We believe that these forms of the virus are now better able to kill immune cells, leading to AIDS. This study will contribute to a greater understanding of how HIV-1 causes AIDS, which is necessary for the development of new drugs to treat HIV-1 infection.