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

Czubala, Magdalena A. ORCID: https://orcid.org/0000-0001-9881-1095, Finsterbusch, Katja, Ivory, Matthew O. ORCID: https://orcid.org/0000-0002-8736-395X, Mitchell, J. Paul, Ahmed, Zahra, Shimauchi, Takatoshi, Karoo, Richard O. S., Coulman, Sion A. ORCID: https://orcid.org/0000-0002-1277-7584, Gateley, Christopher, Birchall, James C. ORCID: https://orcid.org/0000-0001-8521-6924, 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: Pharmacy
Medicine
Publisher: Elsevier
ISSN: 0022-202X
Date of First Compliant Deposit: 3 August 2016
Date of Acceptance: 31 May 2016
Last Modified: 25 Jan 2023 10:45
URI: https://orca.cardiff.ac.uk/id/eprint/93573

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