Envelope glycoprotein determinants of pathogenic, macrophage-tropic HIV-1 and their role in HIV-1 disease progression

人类免疫缺陷病毒1型（HIV-1）导致艾滋病，迄今为止，澳大利亚有2万人感染，全世界有4千万人感染。除了免疫系统的T细胞外，HIV-1还可以感染血液、脑、淋巴结、肺、骨髓、皮肤和脑中发现的单核细胞-巨噬细胞谱系的细胞。能够感染这些细胞的HIV-1毒株被称为嗜巨噬细胞（M-嗜性）毒株。受感染的巨噬细胞是体内产生新HIV-1的主要来源，它们使目前用于治疗HIV-1感染的药物的治疗复杂化，因为感染通常是潜伏的（或休眠的），并且与T细胞不同，它们寿命长，并且可能在其正常寿命期间继续产生新病毒。来自晚期疾病（即AIDS）患者的HIV-1病毒比来自疾病早期（即感染后不久，或在无症状或健康期间）患者的病毒更能感染巨噬细胞。因此，HIV-1感染巨噬细胞的能力增加，即，增强的M嗜性是导致HIV-1感染者发生AIDS的重要因素。然而，是什么原因导致HIV-1增加其感染巨噬细胞的能力并导致艾滋病尚不清楚。该提案旨在确定对增强M嗜性和HIV-1疾病进展至关重要的HIV-1特征。我们希望发现，病毒在感染过程中逐渐改变，可以更紧密地与细胞上的受体分子结合，并需要更少的细胞表面受体进行感染。我们认为，这些形式的HIV-1病毒现在能够更好地感染巨噬细胞，而巨噬细胞表面自然只有少量的受体，并且也可以更好地感染和杀死T细胞，导致艾滋病。这项研究将有助于更好地了解HIV-1如何导致艾滋病，这对于开发治疗HIV-1感染的新药是必要的。

Human immunodeficiency virus type 1 (HIV-1) causes AIDS and, to date, has infected 20 thousand people in Australia and 40 million worldwide. In addition to T-cells of the immune system, HIV-1 can also infect cells of the monocyte-macrophage lineage found in blood, brain, lymph node, lungs, bone marrow, skin and brain. HIV-1 strains that can infect these cells are called macrophage-tropic (M-tropic) strains. Infected macrophages are a major source of new HIV-1 produced in the body, and they complicate therapy by the current drugs used to treat HIV-1 infection because infection is often latent (or dormant) and, unlike T-cells, they are long lived and may continue to produce new virus for the duration of their normal life span. HIV-1 virus from patients with advanced disease (i.e. AIDS) can infect macrophages better than virus from patients at early stages of disease (i.e. just after infection, or during the asymptomatic or healthy period). Therefore, the increased ability of HIV-1 to infect macrophages, i.e., enhanced M-tropism, is an important factor contributing to the development of AIDS in people with HIV-1 infection. However, what causes HIV-1 to increase it's ability to infect macrophages and cause AIDS is unknown. This proposal aims to identify features of HIV-1 that are important for enhanced M-tropism and HIV-1 disease progression. We expect to find that the virus gradually changes during the course of infection to forms that can bind to receptor molecules on the cell more tightly, and to forms that need fewer receptors on the cell surface for infection. We believe that these forms of HIV-1 virus are now better able to infect macrophages, which naturally only have small amounts of receptors on their surface, and also can infect and kill T-cells better, 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.