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了解HIV的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。现在已经证实，某些趋化因子受体，也称为HIV辅助受体，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的巨噬细胞嗜性病毒被RANTES、MIP-1α和MIP-1β抑制，而使用CXCR4的T细胞嗜性病毒被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抑制性趋化因子相比，MDC同时抑制巨噬细胞嗜性和T嗜性病毒分离株。巨噬细胞嗜性分离株在原代巨噬细胞和外周血单核细胞中均受到抑制。这种活性与自然亚型的混合物有关，每一种亚型相对于推测的全长趋化因子具有不同的N末端截断。其他证据表明，至少有一个异构体更喜欢介导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，该系统介导了一种新的血液中艾滋病毒抑制机制。评估这一假说有三个具体目标。首先，我们将在杆状病毒中表达MDC亚型，并鉴定出具有最强抗病毒活性的亚型。这些将被用于第二个目的，以阐明该系统介导的抑制HIV的机制。在第三个目标中，我们将确定可供选择的MDC受体，并确定它们在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同受体，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.