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TGFβ induces a SAMHD1-independent post-entry restriction to HIV-1 infection of human epithelial langerhans cells

Czubala, Magdalena Anna, Finsterbusch, Katja, Ivory, Matthew Owen, Mitchell, J. Paul, Ahmed, Zahra, Shimauchi, Takatoshi, Karoo, Richard O. S., Coulman, Sion A., Gateley, Christopher, Birchall, James Caradoc, Blanchet, Fabien P. and Piguet, Vincent 2016. TGFβ induces a SAMHD1-independent post-entry restriction to HIV-1 infection of human epithelial langerhans cells. Journal of Investigative Dermatology 136 (10) , pp. 1981-1989. 10.1016/j.jid.2016.05.123

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Abstract

Sterile alpha motif (SAM) and histidine-aspartic (HD) domains protein 1 (SAMHD1) was previously identified as a critical post-entry restriction factor to HIV-1 infection in myeloid dendritic cells. Here we show that SAMHD1 is also expressed in epidermis-isolated Langerhans cells (LC), but degradation of SAMHD1 does not rescue HIV-1 or vesicular stomatitis virus G-pseudotyped lentivectors infection in LC. Strikingly, using Langerhans cells model systems (mutz-3-derived LC, monocyte-derived LC [MDLC], and freshly isolated epidermal LC), we characterize previously unreported post-entry restriction activity to HIV-1 in these cells, which acts at HIV-1 reverse transcription, but remains independent of restriction factors SAMHD1 and myxovirus resistance 2 (MX2). We demonstrate that transforming growth factor-β signaling confers this potent HIV-1 restriction in MDLC during their differentiation and blocking of mothers against decapentaplegic homolog 2 (SMAD2) signaling in MDLC restores cells’ infectivity. Interestingly, maturation of MDLC with a toll-like receptor 2 agonist or transforming growth factor-α significantly increases cells’ susceptibility to HIV-1 infection, which may explain why HIV-1 acquisition is increased during coinfection with sexually transmitted infections. In conclusion, we report a SAMHD1-independent post-entry restriction in MDLC and LC isolated from epidermis, which inhibits HIV-1 replication. A better understanding of HIV-1 restriction and propagation from LC to CD4+ T cells may help in the development of new microbicides or vaccines to curb HIV-1 infection at its earliest stages during mucosal transmission.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Pharmacy
Publisher: Elsevier
ISSN: 0022-202X
Date of First Compliant Deposit: 3 August 2016
Date of Acceptance: 31 May 2016
Last Modified: 29 Jun 2019 09:32
URI: http://orca-mwe.cf.ac.uk/id/eprint/93573

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