In Vitro Derived Dendritic Cells trans-Infect CD4 T Cells Primarily with Surface-Bound HIV-1 Virions

King's College London, United Kingdom
PLoS Pathogens (Impact Factor: 7.56). 02/2007; 3(1):e4. DOI: 10.1371/journal.ppat.0030004
Source: PubMed


Author Summary
Dendritic cells (DCs) patrol peripheral mucosal sites, capturing and processing potential pathogens into antigenic peptides for presentation to T cells of lymphoid organs, and thereby initiating an immune response. HIV-1 had been proposed to use DCs as “Trojan horses,” hiding inside the DCs and surviving the degradation pathway to gain access to the lymph nodes and spread to the T cells. Our study challenges this “Trojan horse” model by showing that only HIV-1 virions bound to the surface of DCs, and not internalized virions, are transmitted to T cells. Even when T cells specifically recognized the antigen presented by DCs, the infection of T cells was principally mediated by virions remaining at the surface of the DCs. Interestingly, in this context of antigen-specific recognition, which increases the trafficking toward the immunological synapse of DC internal vesicles, where HIV-1 virions seem to hide, a few internal virions could infect T cells. Our findings suggest that in vivo transmission to T cells of HIV-1 virions captured by DCs should be more sensitive to neutralization than previously expected.

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Available from: Marielle Cavrois,
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    • "Additionally, the data also suggests that the compartment may be intracellular with no access to the extracellular space, rendering it trypsin-resistant. Cavrois et al., recently performed a study in dendritic cells to demonstrate that trans-infection occurred primarily by surface-accessible HIV-1 and suggested that internalized HIV does not play a role in trans-infection [46]. This finding somewhat contradicts that of our own, but may be explained due to the different model and cell type used. "
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    ABSTRACT: Astrocytes are extensively infected with HIV-1 in vivo and play a significant role in the development of HIV-1-associated neurocognitive disorders. Despite their extensive infection, little is known about how astrocytes become infected, since they lack cell surface CD4 expression. In the present study, we investigated the fate of HIV-1 upon infection of astrocytes. Astrocytes were found to bind and harbor virus followed by biphasic decay, with HIV-1 detectable out to 72 hours. HIV-1 was observed to associate with CD81-lined vesicle structures. shRNA silencing of CD81 resulted in less cell-associated virus but no loss of co-localization between HIV-1 and CD81. Astrocytes supported trans-infection of HIV-1 to T-cells without de novo virus production, and the virus-containing compartment required 37°C to form, and was trypsin-resistant. The CD81 compartment observed herein, has been shown in other cell types to be a relatively protective compartment. Within astrocytes, this compartment may be actively involved in virus entry and/or spread. The ability of astrocytes to transfer virus, without de novo viral synthesis suggests they are capable of sequestering and protecting virus and thus, they could potentially facilitate viral dissemination in the CNS.
    PLoS ONE 02/2014; 9(2):e90620. DOI:10.1371/journal.pone.0090620 · 3.23 Impact Factor
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    • "Cell-cell transmission plays an important role in the life cycle of replicating viruses where direct surface transfer can represent a more efficient mode of spread, compared with cell-free infection [1,2]. Surface attachment of particles has been shown to modulate infectivity and provide a reservoir for viral passage between cells [3–6]. For example, while cell-free vesicular stomatitis virus (VSV) is rapidly inactivated in circulation, cell surface retention offers temporary protection from neutralization [7–9]. "
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    ABSTRACT: Many replicating viruses, including HIV-1 and HTLV-1, are efficiently transmitted from the cell surface of actively infected cells upon contact with bystander cells. In a previous study, we reported the prolonged cell surface retention of VSV-G replication-deficient pseudotyped lentivector prior to endocytic entry. However, the competing kinetics of cell surface versus dissociation, neutralization or direct transfer to other cells have received comparatively little attention. Here we demonstrate that the relative efficiency of cell-cell surface transmission can outpace "cell-free" transduction at limiting vector input. This coincides with the prolonged half-life of cell bound vector but occurs, unlike HTLV-1, without evidence for particle aggregation. These studies suggest that cell-surface attachment stabilizes particles and alters neutralization kinetics. Our experiments provide novel insight into the underexplored cell-cell transmission of pseudotyped particles.
    PLoS ONE 09/2013; 8(9):e74925. DOI:10.1371/journal.pone.0074925 · 3.23 Impact Factor
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    • "Each lectin receptor appears to have a unique and distinct function. HIV-1 transfer in trans, through the capture of virus by a CLR, such as DC-SIGN, occurs early in in vitro experiments (Cavrois et al., 2007; Dong et al., 2007; Izquierdo-Useros et al., 2007), and is designated trans-infection. However, DC lectin receptors are important molecules involved in the presentation of foreign antigens. "
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    ABSTRACT: Although dendritic cells (DCs) represent a small cell population in the body, they have been recognized as professional antigen presenting cells and key players of both innate and acquired immunity. The recent expansion of basic knowledge concerning differentiation and function of various DC subsets will greatly help to understand the nature of protective immunity required in designing acquired immunodeficiency syndrome (AIDS) vaccines. However, human immunodeficiency virus (HIV) not only targets CD4(+) T cells but also myeloid cells, including macrophages and DC. When HIV infects DC, its replication is highly restricted in DC. Nevertheless, even a low level of HIV production is sufficient to enhance HIV replication in activated CD4(+) T cells, through antigen presentation activity by HIV-infected DC. Considering how antiviral immunity is initiated and memory response is maintained, such efficient DC-T cell transmission of HIV should play an important role in the disturbed immune responses associated with HIV infection. Recently, accessory proteins encoded by HIV have been shown to interact with various proteins in DC, and thereby affect DC-T cell transmission. In this review, we summarize the current understanding about DC biology, antiviral immune responses and DC restriction factors, all of which will be important issues for the development of an effective AIDS vaccine in the future.
    Frontiers in Microbiology 07/2013; 4:178. DOI:10.3389/fmicb.2013.00178 · 3.99 Impact Factor
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