MACROPHAGE DERIVED CHEMOKINE AND HIV INFECTION

最近发现的HIV感染、趋化因子和趋化因子受体之间的联系为理解HIV发病机制和控制血液感染的免疫机制提供了前所未有的机会。现在已经确定，某些趋化因子受体，也称为HIV共受体，促进HIV进入CD4+宿主细胞，并且它们的同源配体趋化因子，由于正常的受体-配体相互作用而抑制HIV感染。已知的趋化因子系统被HIV根据病毒表型选择性地使用。因此，需要CCR5的嗜巨噬病毒被RANTES、mip -1 α和mip -1 β抑制，而使用CxCR4的嗜T细胞病毒被SDF-1抑制。然而，我们最近对β趋化因子MDC的研究表明，趋化因子与HIV感染之间存在一种新的关系。与其他HIV抑制趋化因子不同，MDC同时抑制嗜巨噬细胞和嗜T病毒分离物。嗜巨噬细胞分离株在原代巨噬细胞和PBMC中均受到抑制。这种活性与天然同工异构体的混合物有关，每个同工异构体相对于假定的全长趋化因子具有不同的N端截断。其他证据表明，至少有一种同种异构体倾向于介导HIV抑制的未知受体。基于这些发现，我们的中心假设是MDC形成了一个独特的趋化因子受体配体系统的一部分，该系统介导了血液中HIV抑制的新机制。将有三个具体的目标来评估这一假设。首先，我们将在杆状病毒中表达MDC亚型，并鉴定出具有最有效抗病毒活性的亚型。这些将在第二个目标中用于阐明该系统介导的HIV抑制机制。在第三个目标中，我们将描述替代MDC受体并定义它们在HIV感染中的作用。这些研究有望揭示趋化因子抑制HIV的新机制，可能涉及一种新的共受体，这通常与巨噬细胞和T细胞的感染有关。

The recently discovered connections between HIV infection, chemokines, and chemokine receptors collectively provide unprecedented opportunities for understanding HIV pathogenesis and immunological mechanisms for controlling infection in the blood. It is now established that certain chemokine receptors, also called HIV co-receptors, facilitate the entry of HIV into CD4+ host cells and that their cognate ligands, chemokines, suppress HIV infection as a result of normal receptor-ligand interactions. The known chemokine systems are used selectively by HIV depending on viral phenotype. Consequently, macrophage-tropic viruses that require CCR5 are suppressed by RANTES, MIP-1alpha and MIP-1beta while T cell tropic viruses that use CxCR4 are suppressed by SDF-1. However, our recent studies with the beta chemokine MDC suggest a novel relationship between chemokines and HIV infection. In contrast with other HIV suppressive chemokines MDC suppresses both macrophage tropic and T tropic virus isolates. The macrophage tropic isolates are inhibited in primary macrophages as well as PBMC. This activity is associated with a mixture of natural isoforms, each with a different N terminal truncation relative to the putative full length chemokine. Other evidence suggests that at least one isoform prefers an unidentified receptor that mediates HIV suppression. Based on these findings, our central hypothesis is that MDC forms part of a unique chemokine receptor-ligand system that mediates a novel mechanism of HIV suppression in the blood. There will be three specific aims to evaluate this hypothesis. In the first, we will express the MDC isoforms in baculovirus and identify ones with the most potent antiviral activities. These will be used in the second aim to elucidate the mechanism of HIV suppression mediated by this system. In the third aim, we will characterize alternative MDC receptors and define their roles in HIV infection. These studies promise to reveal a new mechanism for HIV suppression by chemokines, potentially involving a novel co-receptor, that is commonly related to the infection of macrophages as well as T cells.