TGFβ Induces a SAMHD1-Independent Post-Entry Restriction to HIV-1 Infection of Human Epithelial Langerhans Cells

Czubala, Magdalena; Finsterbusch, Katja; Ivory, Matthew Owen; Mitchell, John P.; Ahmed, Zahra; Shimauchi, Takatoshi; Karoo, R.O.S.; Coulman, Sion; Gateley, Christopher; Birchall, James Caradoc; Blanchet, Fabien P.; Piguet, Vincent

doi:10.1016/j.jid.2016.05.123

Cited by 15 publications

(16 citation statements)

References 58 publications

(55 reference statements)

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“…Depending on the LC preparation/isolation method (4) and HIV-1 load (5), and especially ex vivo (1)(2)(3), infectious virions might be retained by LCs within tetraspanin-rich intracellular compartments (6) and then transferred to CD4 ϩ T cells during the first phase of a process termed trans-infection (7). Although HIV-1 productive infection of LCs is limited (8,9), virions produced de novo are additionally transferred later, during the second phase of trans-infection (7).…”

mentioning

confidence: 99%

Calcitonin Gene-Related Peptide Induces HIV-1 Proteasomal Degradation in Mucosal Langerhans Cells

Bomsel

Ganor

2017

J Virol

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The neuroimmune dialogue between peripheral neurons and Langerhans cells (LCs) within mucosal epithelia protects against incoming pathogens. LCs rapidly internalize human immunodeficiency virus type 1 (HIV-1) upon its sexual transmission and then -infect CD4 T cells. We recently found that the neuropeptide calcitonin gene-related peptide (CGRP), secreted mucosally from peripheral neurons, inhibits LC-mediated HIV-1 -infection. In this study, we investigated the mechanism of CGRP-induced inhibition, focusing on HIV-1 degradation in LCs and its interplay with-infection. We first show that HIV-1 degradation occurs in endolysosomes in untreated LCs, and functionally blocking such degradation with lysosomotropic agents results in increased -infection. We demonstrate that CGRP acts via its cognate receptor and at a viral postentry step to induce faster HIV-1 degradation, but without affecting the kinetics of endolysosomal degradation. We reveal that unexpectedly, CGRP shifts HIV-1 degradation from endolysosomes toward the proteasome, providing the first evidence for functional HIV-1 proteasomal degradation in LCs. Such efficient proteasomal degradation significantly inhibits the first phase of-infection, and proteasomal, but not endolysosomal, inhibitors abrogate CGRP-induced inhibition. Together, our results establish that CGRP controls the HIV-1 degradation mode in LCs. The presence of endogenous CGRP within innervated mucosal tissues, especially during the sexual response, to which CGRP contributes, suggests that HIV-1 proteasomal degradation predominates Hence, proteasomal, rather than endolysosomal, HIV-1 degradation in LCs should be enhanced clinically to effectively restrict HIV-1-infection. During sexual transmission, HIV-1 is internalized and degraded in LCs, the resident antigen-presenting cells in mucosal epithelia. Yet during -infection, infectious virions escaping degradation are transferred to CD4 T cells, the principal HIV-1 targets. We previously found that the neuroimmune dialogue between LCs and peripheral neurons, innervating mucosal epithelia, significantly inhibits -infection via the action of the secreted neuropeptide CGRP on LCs. In this study, we investigated whether CGRP-induced inhibition of-infection is linked to CGRP-controlled HIV-1 degradation in LCs. We show that in untreated LCs, HIV-1 is functionally degraded in endolysosomes. In sharp contrast, we reveal that in CGRP-treated LCs, HIV-1 is diverted toward and degraded via another cytosolic protein degradative pathway, namely, the proteasome. These results establish that CGRP regulates HIV-1 degradation in LCs. As CGRP contributes to the sexual response and present within mucosal epithelia, HIV-1 proteasomal degradation in LCs might predominate and should be enhanced clinically.

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confidence: 99%

Calcitonin Gene-Related Peptide Induces HIV-1 Proteasomal Degradation in Mucosal Langerhans Cells

Bomsel

Ganor

2017

J Virol

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“…To probe antigen presentation induction by the bifunctional conjugates in a different model, we employed in vitro -generated human MUTZ-3 cell line-derived LCs (MUTZ-LCs). The MUTZ-LCs are an established Langerin-expressing model and demonstrate relatively similar binding and internalization kinetics as the Langerin + BLCs ( Supplementary Figures 2A,C–E ) to study pathogen interactions with, for example, HIV ( de Jong et al, 2010 ; Czubala et al, 2016 ). After 30-min stimulation with the mannosylated antigens, the MUTZ-LCs were washed and cocultured with the gp100 280–288 -restricted T cell clone, after which T cell activation was measured as described above.…”

Section: Resultsmentioning

confidence: 99%

Targeting of the C-Type Lectin Receptor Langerin Using Bifunctional Mannosylated Antigens

Hogervorst

Achilli

et al. 2020

Front. Cell Dev. Biol.

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Langerhans cells (LCs) are antigen-presenting cells that reside in the skin. They uniquely express high levels of the C-type lectin receptor Langerin (CD207), which is an attractive target for antigen delivery in immunotherapeutic vaccination strategies against cancer. We here assess a library of 20 synthetic, well-defined mannoside clusters, built up from one, two, and three of six monomannosides, dimannosides, or trimannosides, appended to an oligopeptide backbone, for binding with Langerin using surface plasmon resonance and flow cytometric quantification. It is found that Langerin binding affinity increases with increasing number of mannosides. Hexavalent presentation of the mannosides resulted in binding affinities ranging from 3 to 12 µM. Trivalent presentation of the dimannosides and trimannosides led to Langerin affinity in the same range. The model melanoma gp100 antigenic peptide was subsequently equipped with a hexavalent cluster of the dimannosides and trimannosides as targeting moieties. Surprisingly, although the bifunctional conjugates were taken up in LCs in a Langerin-dependent manner, limited antigen presentation to cytotoxic T cells was observed. These results indicate that targeting glycan moieties on immunotherapeutic vaccines should not only be validated for target binding, but also on the continued effects on biology, such as antigen presentation to both CD8 + and CD4 + T cells.

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“…These include TRIM-5a, APOBEC3G/3F, BST-2 (also known as tetherin, CD317, or HM1.24), and SAMHD1 (Ahmed et al, 2013). SAMHD1 was identified as a critical postentry restriction factor that limits HIV-1 infection in myeloid DCs, but not in Langerhans cells, via depletion of the cellular deoxynucleoside triphosphate pool, which inhibits reverse transcription of viral RNA (Czubala et al, 2016;Goldstone et al, 2011;Lahouassa et al, 2012). It has also been reported that SAMHD1 can limit HTLV-1 infection in monocytes (Sze et al, 2013), but this remains controversial (Gramberg et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Dendritic Cells Promote the Spread of Human T-Cell Leukemia Virus Type 1 via Bidirectional Interactions with CD4+ T Cells

Shimauchi

Caucheteux

Finsterbusch

et al. 2019

Journal of Investigative Dermatology

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Human T-cell leukemia virus type 1 (HTLV-1) propagates within and between individuals via cell-to-cell transmission, and primary infection typically occurs across juxtaposed mucosal surfaces during breastfeeding or sexual intercourse. It is therefore likely that dendritic cells (DCs) are among the first potential targets for HTLV-1. However, it remains unclear how DCs contribute to virus transmission and dissemination in the early stages of infection. We show that an HTLV-1-infected cell line (MT-2) and naturally infected CD4 T cells transfer p19 viral particles to the surface of allogeneic DCs via cell-to-cell contacts. Similarly organized cell-to-cell contacts also facilitate DC-mediated transfer of HTLV-1 to autologous CD4 T cells. These findings shed light on the cellular structures involved in anterograde and retrograde transmission and suggest a key role for DCs in the natural history and pathogenesis of HTLV-1 infection.

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TGFβ Induces a SAMHD1-Independent Post-Entry Restriction to HIV-1 Infection of Human Epithelial Langerhans Cells

Cited by 15 publications

References 58 publications

Calcitonin Gene-Related Peptide Induces HIV-1 Proteasomal Degradation in Mucosal Langerhans Cells

Calcitonin Gene-Related Peptide Induces HIV-1 Proteasomal Degradation in Mucosal Langerhans Cells

Targeting of the C-Type Lectin Receptor Langerin Using Bifunctional Mannosylated Antigens

Dendritic Cells Promote the Spread of Human T-Cell Leukemia Virus Type 1 via Bidirectional Interactions with CD4+ T Cells

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