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    ABSTRACT: Chemokines are a family of low molecular weight proteins with an essential role in leukocyte trafficking during both homeostasis and inflammation. The CC class of chemokines consists of at least 28 members (CCL1-28) that signal through 10 known chemokine receptors (CCR1-10). CC chemokine receptors are expressed predominantly by T cells and monocyte-macrophages, cell types associated predominantly with chronic inflammation occurring over weeks or years. Chronic inflammatory diseases including rheumatoid arthritis, atherosclerosis, and metabolic syndrome are characterized by continued leukocyte infiltration into the inflammatory site, driven in large part by excessive chemokine production. Over years or decades, persistent inflammation may lead to loss of tissue architecture and function, causing severe disability or, in the case of atherosclerosis, fatal outcomes such as myocardial infarction or stroke. Despite the existence of several clinical strategies for targeting chronic inflammation, these diseases remain significant causes of morbidity and mortality globally, with a concomitant economic impact. Thus, the development of novel therapeutic agents for the treatment of chronic inflammatory disease continues to be a priority. In this review we introduce CC chemokine receptors as critical mediators of chronic inflammatory responses and explore their potential role as pharmacological targets. We discuss functions of individual CC chemokine receptors based on in vitro pharmacological data as well as transgenic animal studies. Focusing on three key forms of chronic inflammation-rheumatoid arthritis, atherosclerosis, and metabolic syndrome-we describe the pathologic function of CC chemokine receptors and their possible relevance as therapeutic targets.
    Full-text · Article · Dec 2013 · Pharmacological reviews
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    ABSTRACT: Macrophage infection is considered to play an important role in HIV-1 pathogenesis and persistence. Using a primary cell-based co-culture model we show that monocyte-derived macrophages (MDM) efficiently transmit a high multiplicity HIV-1 infection to autologous CD4(+) T cells through a viral envelope glycoprotein (Env)-receptor and actin-dependent virological synapse (VS), facilitated by interactions between ICAM-1 and LFA-1. VS-mediated transmission by MDM results in high levels of T cell HIV-1 integration and is 1-2 orders of magnitude more efficient than cell-free infection. This mode of cell-to-cell transmission is broadly susceptible to the activity of CD4 binding site (CD4bs) and glycan or glycopeptide epitope-specific broadly neutralizing monoclonal antibodies (bNmAbs), but shows resistance to bNmAbs targeting the Env gp41 subunit membrane-proximal external region. These data define for the first time the structure and function of the macrophage-to-T cell VS and have important implications for bNmAb activity in HIV-1 prophylaxis and therapy.
    Full-text · Article · Dec 2013 · Journal of Virology
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    ABSTRACT: CP110 is a conserved centriole protein implicated in the regulation of cell division, centriole duplication, and centriole length and in the suppression of ciliogenesis. Surprisingly, we report that mutant flies lacking CP110 (CP110Δ) were viable and fertile and had no obvious defects in cell division, centriole duplication, or cilia formation. We show that CP110 has at least three functions in flies. First, it subtly influences centriole length by counteracting the centriole-elongating activity of several centriole duplication proteins. Specifically, we report that centrioles are ∼10% longer than normal in CP110Δ mutants and ∼20% shorter when CP110 is overexpressed. Second, CP110 ensures that the centriolar microtubules do not extend beyond the distal end of the centriole, as some centriolar microtubules can be more than 50 times longer than the centriole in the absence of CP110. Finally, and unexpectedly, CP110 suppresses centriole overduplication induced by the overexpression of centriole duplication proteins. These studies identify novel and surprising functions for CP110 in vivo in flies.
    Full-text · Article · Dec 2013 · The Journal of Cell Biology
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