Groot, F., Welsch, S. & Sattentau, Q. J. Efficient HIV-1 transmission from macrophages to T cells across transient virological synapses. Blood 111, 4660-4663

Sir William Dunn School of Pathology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
Blood (Impact Factor: 10.45). 06/2008; 111(9):4660-3. DOI: 10.1182/blood-2007-12-130070
Source: PubMed


Macrophages are reservoirs of HIV-1 infection, proposed to transmit virus to CD4(+) T cells, the primary target of the virus. Here we report that human monocyte-derived macrophages (MDMs) rapidly spread HIV-1 to autologous CD4(+) T cells resulting in productive infection. Transmission takes place across transient adhesive contacts between T cells and MDMs, which have the features of a virological synapse including copolarization of CD4 on the T cell with HIV-1 Gag and Env on the macrophage. We propose that an infected MDM can infect at least one T cell every 6 hours. Since HIV-1-infected macrophages can survive for many weeks, these results highlight the central role played by macrophages in HIV-1 infection and pathogenesis.

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    • "These FV3-infected cells exhibited small numbers of intracellular viral particles, implying that FV3 may employ mononuclear phagocytes as a reservoir for dissemination. FV3-macrophage interaction is reminiscent of the HIV-macrophage relationship in which viral particles accumulate within the myeloid cells as a mechanism of dissemination (Coiras et al. 2009 ; Goodenow et al. 2003 ; Gousset et al. 2008 ; Groot et al. 2008 ). Interestingly, several of these FV3-infected peritoneal macrophages not only contained cytoplasmic virions, they also shed virions into the extracellular milieu (Morales et al. 2010 ), confi rming that these cells likely function as both reservoirs and vectors of viral dissemination within their hosts. "

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    • "Performed as described previously in Groot et al . ( 2008 ) . Cells were fixed in 4% paraformaldehyde ( PFA ) for 1 hr , quenched with 50 mM NH 4 Cl in PBS for 20 min , nuclei stained with 1 mg / ml Hoechst in PBS , and cells permeabilized in wash buffer ( WB , 0 . 1% saponin / 0 . 5% BSA in PBS + 5% pooled human and goat serum ) . Samples were stained for CD3 ( UCHT1 - IgG1 , BD Biosci - ence"
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    ABSTRACT: Macrophages contribute to HIV-1 pathogenesis by forming a viral reservoir and mediating neurological disorders. Cell-free HIV-1 infection of macrophages is inefficient, in part due to low plasma membrane expression of viral entry receptors. We find that macrophages selectively capture and engulf HIV-1-infected CD4(+) T cells leading to efficient macrophage infection. Infected T cells, both healthy and dead or dying, were taken up through viral envelope glycoprotein-receptor-independent interactions, implying a mechanism distinct from conventional virological synapse formation. Macrophages infected by this cell-to-cell route were highly permissive for both CCR5-using macrophage-tropic and otherwise weakly macrophage-tropic transmitted/founder viruses but restrictive for nonmacrophage-tropic CXCR4-using virus. These results have implications for establishment of the macrophage reservoir and HIV-1 dissemination in vivo. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Nov 2014 · Cell Host & Microbe
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    • "The HIV-1 T cell virological synapse is defined by enrichment of HIV-1 Gag and Env at sites of cell-cell contact and is dependent on receptor-mediated intercellular interactions. Indeed, studies have shown that antibodies against HIV-1 Env that target the CD4 binding site can access the cell-cell interface and inhibit synapse formation [5,9,12]. Therefore, having shown that both J3 and J3-Fc can block cell-cell spread we next investigated whether these antibodies inhibit synapse formation. Immunofluorescence microscopy staining revealed that both J3 and J3-Fc could be detected at intercellular junctions formed between HIV-1 infected and uninfected T cells, engage HIV-1 Env and stain the cell-cell interface (Figure 5C). "
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    ABSTRACT: Direct cell-cell spread of HIV-1 is a very efficient mode of viral dissemination, with increasing evidence suggesting that it may pose a considerable challenge to controlling viral replication in vivo. Much current vaccine research involves the study of broadly neutralising antibodies (bNabs) that arise during natural infection with the aims of eliciting such antibodies by vaccination or incorporating them into novel therapeutics. However, whether cell-cell spread of HIV-1 can be effectively targeted by bNabs remains unclear, and there is much interest in identifying antibodies capable of efficiently neutralising virus transmitted by cell-cell contact. In this study we have tested a panel of bNAbs for inhibition of cell-cell spread, including some not previously evaluated for inhibition of this mode of HIV-1 transmission. We found that three CD4 binding site antibodies, one from an immunised llama (J3) and two isolated from HIV-1-positive patients (VRC01 and HJ16) neutralised cell-cell spread between T cells, while antibodies specific for glycan moieties (2G12, PG9, PG16) and the MPER (2F5) displayed variable efficacy. Notably, while J3 displayed a high level of potency during cell-cell spread we found that the small size of the llama heavy chain-only variable region (VHH) J3 is not required for efficient neutralisation since recombinant J3 containing a full-length human heavy chain Fc domain was significantly more potent. J3 and J3-Fc also neutralised cell-cell spread of HIV-1 from primary macrophages to CD4+ T cells. In conclusion, while bNabs display variable efficacy at preventing cell-cell spread of HIV-1, we find that some CD4 binding site antibodies can inhibit this mode of HIV-1 dissemination and identify the recently described llama antibody J3 as a particularly potent inhibitor. Effective neutralisation of cell-cell spread between physiologically relevant cell types by J3 and J3-Fc supports the development of VHH J3 nanobodies for therapeutic or prophylactic applications.
    Full-text · Article · Oct 2014 · Retrovirology
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