DC-SIGN on B Lymphocytes Is Required For Transmission of HIV-1 to T Lymphocytes

Rappocciolo, Giovanna; Piazza, Paolo; Fuller, Craig L.; Reinhart, Todd A.; Watkins, Simon C.; Rowe, David; Jais, Mariel; Gupta, Phalguni; Rinaldo, Charles R.

doi:10.1371/journal.ppat.0020070

Cited by 100 publications

(122 citation statements)

References 43 publications

(63 reference statements)

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“…Our results could have important consequences in infection by HIV-1, and might suggest a role for miR-155 in making subjects more or less susceptible to infection. Interestingly, there are several studies reporting the possible use of DC-SIGN blocking agents that aim to stop HIV-1 infection (42)(43)(44)(45). Thus, miR-155 could be a new therapeutic target that could help prevent entrance of HIV-1 through binding of DC-SIGN.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-155 Modulates the Pathogen Binding Ability of Dendritic Cells (DCs) by Down-regulation of DC-specific Intercellular Adhesion Molecule-3 Grabbing Non-integrin (DC-SIGN)

Martínez-Nuñez

Louafi

Friedmann

et al. 2009

Journal of Biological Chemistry

194

171

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MicroRNA-155 (miR-155) has been involved in the response to inflammation in macrophages and lymphocytes. Here we show how miR-155 participates in the maturation of human dendritic cells (DC) and modulates pathogen binding by downregulating DC-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN), after directly targeting the transcription factor PU.1. During the maturation of DCs, miR-155 increases up to 130-fold, whereas PU.1 protein levels decrease accordingly. We establish that human PU.1 is a direct target for miR-155 and localize the target sequence for miR-155 in the 3-untranslated region of PU.1. Also, overexpression of miR-155 in the THP1 monocytic cell line decreases PU.1 protein levels and DC-SIGN at both the mRNA and protein levels. We prove a link between the down-regulation of PU.1 and reduced transcriptional activity of the DC-SIGN promoter, which is likely to be the basis for its reduced mRNA expression, after miR-155 overexpression. Finally, we show that, by reducing DC-SIGN in the cellular membrane, miR-155 is involved in regulating pathogen binding as dendritic cells exhibited the lower binding capacity for fungi and HIV protein gp-120 when the levels of miR-155 were higher. Thus, our results suggest a mechanism by which miR-155 regulates proteins involved in the cellular immune response against pathogens that could have clinical implications in the way pathogens enter the human organism.MicroRNAs have emerged as important regulators of key cellular processes. They consist of endogenous small, non-coding RNA molecules of about 19 -22 nucleotides in length (1), which regulate mRNAs in a post-transcriptional manner. They bind to the 3Ј-untranslated regions of their target mRNAs and exert their function in two ways: mainly blocking the translation and also inducing their cleavage in a similar fashion to small interfering RNAs (2). MicroRNAs are initially expressed as long immature pri-microRNAs, which are processed in the nucleus into the precursor pre-microRNAs and finally matured by Dicer in the cytoplasm into the functional 19 -22-nucleotide long microRNAs, which are then incorporated into the RNAinduced silencing complex (1).The role of microRNAs is being intensively studied in many different fields such as fetal development and the immune system. One of the miRNAs that appears to play a particularly important role in the immune system is microRNA-155 (miR-155), 3 the expression of which is induced by inflammatory signals such as exposure to antigen, Toll-like receptor ligands, or interferon ␥ stimulation in T-cells, B-cells, and macrophages, respectively (3, 4). miR-155 knock-out mice show aberrant immune functions including defective B and T cell immunity and abnormal function of antigen-presenting cells (4, 5). These mutant mice exhibit an imbalance in the immune Th1/Th2 response, with the CD4ϩ T cells biased toward Th2 differentiation (4). A lack of miR-155 also leads to a failure in production of high-affinity IgG 1 antibodies by murine B-cells (28). This effect has b...

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Section: Discussionmentioning

confidence: 99%

MicroRNA-155 Modulates the Pathogen Binding Ability of Dendritic Cells (DCs) by Down-regulation of DC-specific Intercellular Adhesion Molecule-3 Grabbing Non-integrin (DC-SIGN)

Martínez-Nuñez

Louafi

Friedmann

et al. 2009

Journal of Biological Chemistry

194

171

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“…ϩ T cells by both X4-and R5-tropic HIV-1 (6). By contrast, the examination of HIV-1 transmission by L-SIGN /DC-SIGNR has been more limited.…”

Section: Hiv-1 Transmission (46) Recent Studies Have Also Shown Thatmentioning

confidence: 99%

“…(1-4), activated B cells (5,6), and some subsets of macrophages (7,8). By contrast, L-SIGN, a related lectin (also known as DC-SIGNR), is expressed on liver sinusoidal endothelial cells, the lung, and in lymph nodes (9 -11).…”

mentioning

confidence: 99%

“…ϩ T cells (6), and up to 90% of HIV-1 binding to human mucosal tissue explants has been attributed to DC-SIGN-expressing cells (31). DC-SIGN expressed by in vitro differentiated immature monocyte-derived DCs confers signifi-cant HIV-1 binding and transmission by these cells (32)(33)(34), which can be recapitulated through ectopic expression of DC-SIGN in Raji B cells (35).…”

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confidence: 99%

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HIV-1 Transmission by Dendritic Cell-specific ICAM-3-grabbing Nonintegrin (DC-SIGN) Is Regulated by Determinants in the Carbohydrate Recognition Domain That Are Absent in Liver/Lymph Node-SIGN (L-SIGN)

Chung

Breun

Bashirova

et al. 2010

Journal of Biological Chemistry

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“…DC-SIGN has been shown to be a key receptor in DC-mediated transfer of HIV infectivity (31)(32)(33). SP-A and recombinant soluble DC-SIGN were immobilized to individual flow cells of a BIACore chip and the binding to HIV BaL particles was measured by changes in surface plasmon resonance.…”

Section: Effects Of Ph On the Binding Of Sp-a And Dc-sign To Hivmentioning

confidence: 99%

Surfactant Protein A Binds to HIV and Inhibits Direct Infection of CD4+ Cells, but Enhances Dendritic Cell-Mediated Viral Transfer

Gaiha

Dong

Palaniyar

et al. 2008

The Journal of Immunology

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The identification of surfactant protein A (SP-A) as an important innate immune factor of the lungs, amniotic fluid, and the vaginal tract suggests that it could play an important role during various stages of HIV disease progression and transmission. Therefore, we examined whether SP-A could bind to HIV and also had any effect on viral infectivity. Our data demonstrate that SP-A binds to HIV in a calcium-dependent manner that is inhibitable by mannose and EDTA. Affinity capture of the HIV viral lysate reveals that SP-A targets the envelope glycoprotein of HIV (gp120), which was confirmed by ELISA using recombinant gp120. Digestion of gp120 with endoglycosidase H abrogates the binding of SP-A, indicating that the high mannose structures on gp120 are the target of the collectin. Infectivity studies reveal that SP-A inhibits the infection of CD4+ T cells by two strains of HIV (BaL, IIIB) by >80%. Competition assays with CD4 and mAbs F105 and b12 suggest that SP-A inhibits infectivity by occlusion of the CD4-binding site. Studies with dendritic cells (DCs) demonstrate that SP-A enhances the binding of gp120 to DCs, the uptake of viral particles, and the transfer of virus from DCs to CD4+ T cells by >5-fold at a pH representative of the vaginal tract. Collectively, these results suggest that SP-A acts as a dual modulator of HIV infection by protecting CD4+ T cells from direct infection but enhancing the transfer of infection to CD4+ T cells mediated by DCs.

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DC-SIGN on B Lymphocytes Is Required For Transmission of HIV-1 to T Lymphocytes

Cited by 100 publications

References 43 publications

MicroRNA-155 Modulates the Pathogen Binding Ability of Dendritic Cells (DCs) by Down-regulation of DC-specific Intercellular Adhesion Molecule-3 Grabbing Non-integrin (DC-SIGN)

MicroRNA-155 Modulates the Pathogen Binding Ability of Dendritic Cells (DCs) by Down-regulation of DC-specific Intercellular Adhesion Molecule-3 Grabbing Non-integrin (DC-SIGN)

HIV-1 Transmission by Dendritic Cell-specific ICAM-3-grabbing Nonintegrin (DC-SIGN) Is Regulated by Determinants in the Carbohydrate Recognition Domain That Are Absent in Liver/Lymph Node-SIGN (L-SIGN)

Surfactant Protein A Binds to HIV and Inhibits Direct Infection of CD4+ Cells, but Enhances Dendritic Cell-Mediated Viral Transfer

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