Infection of Specific Dendritic Cells by CCR5-Tropic Human Immunodeficiency Virus Type 1 Promotes Cell-Mediated Transmission of Virus Resistant to Broadly Neutralizing Antibodies

Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bldg. 40, Rm. 4502, MSC-3005, 40 Convent Dr., Bethesda, MD 20892-3005, USA.
Journal of Virology (Impact Factor: 4.44). 12/2004; 78(21):11980-7. DOI: 10.1128/JVI.78.21.11980-11987.2004
Source: PubMed


The tropism of human immunodeficiency virus type 1 for chemokine receptors plays an important role in the transmission of
AIDS. Although CXCR4-tropic virus is more cytopathic for T cells, CCR5-tropic strains are transmitted more frequently in humans
for reasons that are not understood. Phenotypically immature myeloid dendritic cells (mDCs) are preferentially infected by
CCR5-tropic virus, in contrast to mature mDCs, which are not susceptible to infection but instead internalize virus into a
protected intracellular compartment and enhance the infection of T cells. Here, we define a mechanism to explain preferential
transmission of CCR5-tropic viruses based on their interaction with mDCs and sensitivity to neutralizing antibodies. Infected
immature mDCs differentiated normally and were found to enhance CCR5-tropic but not CXCR4-tropic virus infection of T cells
even in the continuous presence of neutralizing antibodies. Infectious synapses also formed normally in the presence of such
antibodies. Infection of immature mDCs by CCR5-tropic virus can therefore establish a pool of infected cells that can efficiently
transfer virus at the same time that they protect virus from antibody neutralization. This property of DCs may enhance infection,
contribute to immune evasion, and could provide a selective advantage for CCR5-tropic virus transmission.

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    • "To further investigate the exact role(s) of miR-155 on cocaine mediated modulation of HIV-1 replication, we transfected MDDCs with either miR-155 mimic or anti-miR-155, followed by infection with HIV-1 and/or cocaine treatment. Total RNA was extracted and amplified by qRT-PCR for HIV-1 LTR/R-U5 [31], [39], [40]. miR-155 over expression significantly suppressed HIV-1 replication whereas anti-miR-155 transfection in combination with HIV-1 infection enhanced HIV-1 replication compared to non-transfected HIV-1 control (Fig. 3). "
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    ABSTRACT: Cocaine and other drugs of abuse increase HIV-induced immunopathogenesis; and neurobiological mechanisms of cocaine addiction implicate a key role for microRNAs (miRNAs), single-stranded non-coding RNAs that regulate gene expression and defend against viruses. In fact, HIV defends against miRNAs by actively suppressing the expression of polycistronic miRNA cluster miRNA-17/92, which encodes miRNAs including miR-20a. IFN-g production by natural killer cells is regulated by miR-155 and this miRNA is also critical to dendritic cell (DC) maturation. However, the impact of cocaine on miR-155 expression and subsequent HIV replication is unknown. We examined the impact of cocaine on two miRNAs, miR-20a and miR-155, which are integral to HIV replication, and immune activation. Using miRNA isolation and analysis, RNA interference, quantitative real time PCR, and reporter assays we explored the effects of cocaine on miR-155 and miR-20 in the context of HIV infection. Here we demonstrate using monocyte-derived dendritic cells (MDCCs) that cocaine significantly inhibited miR-155 and miR-20a expression in a dose dependent manner. Cocaine and HIV synergized to lower miR-155 and miR-20a in MDDCs by 90%. Cocaine treatment elevated LTR-mediated transcription and PU.1 levels in MDCCs. But in context of HIV infection, PU.1 was reduced in MDDCs regardless of cocaine presence. Cocaine increased DC-SIGN and and decreased CD83 expression in MDDC, respectively. Overall, we show that cocaine inhibited miR-155 and prevented maturation of MDDCs; potentially, resulting in increased susceptibility to HIV-1. Our findings could lead to the development of novel miRNA-based therapeutic strategies targeting HIV infected cocaine abusers.
    Full-text · Article · Dec 2013 · PLoS ONE
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    • "Cell-mediated infection of a target cell by HIV-1 can occur via the formation of virological synapses with productively infected cells [11,19,20] or through infectious synapses with non-infected DC harboring HIV-1 [12,21]. Although the virological synapse has been extensively studied in the context of T cell-T cell viral transmission [11,20,22], infected immature DC or macrophages can act alternatively as effector cells [23-26], while uninfected DC can also act as target cells [25,27]. Cell adhesion in virological synapses is driven by the engagement of the CD4 molecule on the target cell with the viral Env on the surface of HIV-1-infected donor cells, which increases conjugate formation and favors viral transfer [11,20,22,27]. "
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    ABSTRACT: Background Since cell-mediated infection of human immunodeficiency virus type 1 (HIV-1) is more efficient than cell-free infection, cell-to-cell propagation plays a crucial role in the pathogenesis of HIV-1 infection. Transmission of HIV-1 is enabled by two types of cellular contacts, namely, virological synapses between productively infected cells and uninfected target cells and infectious synapses between uninfected dendritic cells (DC) harboring HIV-1 and uninfected target cells. While virological synapses are driven by expression of the viral envelope glycoprotein on the cell surface, little is known about the role of envelope glycoprotein during contact between DC and T cells. We explored the contribution of HIV-1 envelope glycoprotein, adhesion molecules, and antigen recognition in the formation of conjugates comprising mature DC (mDC) and CD4+ T cells in order to further evaluate their role in mDC-mediated HIV-1 transmission at the immunological synapse. Results Unlike virological synapse, HIV-1 did not modulate the formation of cell conjugates comprising mDC harboring HIV-1 and non-activated primary CD4+ T cells. Disruption of interactions between ICAM-1 and LFA-1, however, resulted in a 60% decrease in mDC-CD4+ T-cell conjugate formation and, consequently, in a significant reduction of mDC-mediated HIV-1 transmission to non-activated primary CD4+ T cells (p < 0.05). Antigen recognition or sustained MHC-TcR interaction did not enhance conjugate formation, but significantly boosted productive mDC-mediated transmission of HIV-1 (p < 0.05) by increasing T-cell activation and proliferation. Conclusions Formation of the infectious synapse is independent of the presence of the HIV-1 envelope glycoprotein, although it does require an interaction between ICAM-1 and LFA-1. This interaction is the main driving force behind the formation of mDC-CD4+ T-cell conjugates and enables transmission of HIV-1 to CD4+ T cells. Moreover, antigen recognition boosts HIV-1 replication without affecting the frequency of cellular conjugates. Our results suggest a determinant role for immune activation driven by mDC-CD4+ T-cell contacts in viral dissemination and that this activation likely contributes to the pathogenesis of HIV-1 infection.
    Full-text · Article · Apr 2013 · Retrovirology
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    • "This observation prompted the study of cell-to-cell transmission. The inability of neutralizing antibodies that block cell-free virus to interfere with spreading of certain viruses in cultures provided early evidence for cell-to-cell spread [10], [11], [12], [13], [14]. In addition, the ability of neurotropic viruses to spread along neurons or the ability of Vaccinia virus to induce actin tails that could propel viral particles to neighboring cells supported viral spread by cell-cell contact [15], [16], [17], [18], [19]. "
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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.
    Full-text · Article · Jan 2013 · PLoS ONE
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