HIV-1-infected Blood Mononuclear Cells Form an Integrin- and Agrin-dependent Viral Synapse to Induce Efficient HIV-1 Transcytosis across Epithelial Cell Monolayer

Entrée Muqueuse du VIH et Immunité muqueuse, Departement de Biologie Cellulaire, Institut Cochin, CNRS, INSERM, Université René Descartes, 75014 Paris, France.
Molecular Biology of the Cell (Impact Factor: 4.47). 10/2005; 16(9):4267-79. DOI: 10.1091/mbc.E05-03-0192
Source: PubMed


The heparan sulfate proteoglycan agrin and adhesion molecules are key players in the formation of neuronal and immune synapses that evolved for efficient communication at the sites of cell-cell contact. Transcytosis of infectious virus across epithelial cells upon contact between HIV-1-infected cells and the mucosal pole of the epithelial cells is one mechanism for HIV-1 entry at mucosal sites. In contrast, transcytosis of cell-free HIV-1 is not efficient. A synapse between HIV-1-infected cells and the mucosal epithelial surface that resembles neuronal and immune synapses is visualized by electron microscopy. We have termed this the "viral synapse." Similarities of the viral synapse also extend to the functional level. HIV-1-infected cell-induced transcytosis depends on RGD-dependent integrins and efficient cell-free virus transcytosis is inducible upon RGD-dependent integrin cross-linking. Agrin appears differentially expressed at the apical epithelial surface and acts as an HIV-1 attachment receptor. Envelope glycoprotein subunit gp41 binds specifically to agrin, reinforcing the interaction of gp41 to its epithelial receptor galactosyl ceramide.

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    • "HIV spreading in cell culture has also been observed to be resistant to neutralizing antibodies and to the antiviral drug tenofovir, which efficiently inhibit cell-free HIV [12], [20], [23], [24]. The current concept to explain these observations can be described by the virological synapse, a virus-induced synaptic-like contact between infected cells and uninfected target cells [23], [25], [26], [27], [28], [29], [30], [31]. The virological synapse is believed to efficiently coordinate several steps of the viral life cycle [1], [3], [4]. "
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    ABSTRACT: Virus transmission can occur either by a cell-free mode through the extracellular space or by cell-to-cell transmission involving direct cell-to-cell contact. The factors that determine whether a virus spreads by either pathway are poorly understood. Here, we assessed the relative contribution of cell-free and cell-to-cell transmission to the spreading of the human immunodeficiency virus (HIV). We demonstrate that HIV can spread by a cell-free pathway if all the steps of the viral replication cycle are efficiently supported in highly permissive cells. However, when the cell-free path was systematically hindered at various steps, HIV transmission became contact-dependent. Cell-to-cell transmission overcame barriers introduced in the donor cell at the level of gene expression and surface retention by the restriction factor tetherin. Moreover, neutralizing antibodies that efficiently inhibit cell-free HIV were less effective against cell-to-cell transmitted virus. HIV cell-to-cell transmission also efficiently infected target T cells that were relatively poorly susceptible to cell-free HIV. Importantly, we demonstrate that the donor and target cell types influence critically the extent by which cell-to-cell transmission can overcome each barrier. Mechanistically, cell-to-cell transmission promoted HIV spread to more cells and infected target cells with a higher proviral content than observed for cell-free virus. Our data demonstrate that the frequently observed contact-dependent spread of HIV is the result of specific features in donor and target cell types, thus offering an explanation for conflicting reports on the extent of cell-to-cell transmission of HIV.
    PLoS ONE 01/2013; 8(1):e53138. DOI:10.1371/journal.pone.0053138 · 3.23 Impact Factor
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    • "Moreover, the transmitted virus was able to infect human DCs located immediately below the epithelial barrier (Martin-Latil et al., 2012). HIV-1 has also been shown to be capable of crossing intact oral and intestinal epithelial barriers by transcytosis and to be capable of infecting DCs, macrophages, and CD4+ T cells on the other side of those barriers in both ex vivo studies using tissue explants and in vitro studies (Bomsel, 1997; Alfsen et al., 2005; Tugizov et al., 2012). "
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    ABSTRACT: The deltaretroviruses human T cell lymphotropic virus type 1 (HTLV-1) and human T cell lymphotropic virus type 2 (HTLV-2) have long been believed to differ from retroviruses in other genera by their mode of transmission. While other retroviruses were thought to primarily spread by producing cell-free particles that diffuse through extracellular fluids prior to binding to and infecting target cells, HTLV-1 and HTLV-2 were believed to transmit the virus solely by cell-cell interactions. This difference in transmission was believed to reflect the fact that, relative to other retroviruses, the cell-free virions produced by HTLV-infected cells are very poorly infectious. Since HTLV-1 and HTLV-2 are primarily found in T cells in the peripheral blood, spread of these viruses was believed to occur between infected and uninfected, T cells, although little was known about the cellular and viral proteins involved in this interaction. Recent studies have revealed that the method of transmission of HTLV is not unique: other retroviruses including human immunodeficiency virus (HIV) are also transmitted from cell-to-cell, and this method is dramatically more efficient than cell-free transmission. Moreover, cell-cell transmission of HTLV-1, as well as HIV, can occur following interactions between dendritic cells and T cells, as well as between T cells. Conversely, other studies have shown that cell-free HTLV-1 is not as poorly infectious as previously thought, since it is capable of infecting certain cell types. Here we summarize the recent insights about the mechanisms of cell-cell transmission of HTLV-1 and other retroviruses. We also review in vitro and in vivo studies of infection and discuss how these finding may relate to the spread of HTLV-1 between individuals.
    Frontiers in Microbiology 10/2012; 3:378. DOI:10.3389/fmicb.2012.00378 · 3.99 Impact Factor
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    • "In contrast to cell-free HIV-1 infection, cell-associated infection arises from direct cell-to-cell transfer of virus to susceptible target cells. Cell-to-cell spread of HIV-1 in culture is significantly more efficient than spread of cell-free virus and involves formation of a transient yet complex virological synapse [14]–[17], which is more difficult to neutralize [15]. "
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    ABSTRACT: Transmission of HIV-1 during breastfeeding is a significant source of new pediatric infections in sub-Saharan Africa. Breast milk from HIV-positive mothers contains both cell-free and cell-associated virus; however, the impact of breast milk on HIV-1 infectivity remains poorly understood. In the present study, breast milk was collected from HIV-positive and HIV-negative Tanzanian women attending antenatal clinics in Dar es Salaam. Milk was analyzed for activity in vitro against both cell-free and cell-associated HIV-1. Potent inhibition of cell-free R5 and X4 HIV-1 occurred in the presence of milk from all donors regardless of HIV-1 serostatus. Inhibition of cell-free HIV-1 infection positively correlated with milk levels of sialyl-Lewis(X) from HIV-positive donors. In contrast, milk from 8 of 16 subjects enhanced infection with cell-associated HIV-1 regardless of donor serostatus. Milk from two of these subjects contained high levels of multiple pro-inflammatory cytokines including TNFα, IL-1β, IL-6, IL-8, MIP-1α, MIP-1β, MCP-1 and IP-10, and enhanced cell-associated HIV-1 infection at dilutions as high as 1∶500. These findings indicate that breast milk contains innate factors with divergent activity against cell-free and cell-associated HIV-1 in vitro. Enhancement of cell-associated HIV-1 infection by breast milk may be associated with inflammatory conditions in the mother and may contribute to infant infection during breastfeeding.
    PLoS ONE 08/2012; 7(8):e43815. DOI:10.1371/journal.pone.0043815 · 3.23 Impact Factor
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