title: TGFβ Induces a SAMHD1-Independent Post-Entry Restriction to HIV-1 Infection of Human Epithelial Langerhans Cells.
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.
authors.affiliation: Department of Dermatology and Academic Wound Healing, Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Magdalena A
authors.initials: MA
authors.lastname: Czubala
authors.affiliation: Department of Dermatology and Academic Wound Healing, Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Katja
authors.initials: K
authors.lastname: Finsterbusch
authors.affiliation: Department of Dermatology and Academic Wound Healing, Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK; Cardiff University School of Pharmacy and Pharmaceutical Sciences, Cardiff CF10 3NB, UK.
authors.forename: Matthew O
authors.initials: MO
authors.lastname: Ivory
authors.affiliation: Department of Dermatology and Academic Wound Healing, Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: J Paul
authors.initials: JP
authors.lastname: Mitchell
authors.affiliation: Department of Dermatology and Academic Wound Healing, Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Ahmed
authors.affiliation: Department of Dermatology and Academic Wound Healing, Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Shimauchi
authors.affiliation: Spire Cardiff Hospital, Cardiff CF23 8XL, UK.
authors.forename: Richard O S
authors.initials: ROS
authors.lastname: Karoo
authors.affiliation: Cardiff University School of Pharmacy and Pharmaceutical Sciences, Cardiff CF10 3NB, UK.
authors.forename: Sion A
authors.initials: SA
authors.lastname: Coulman
authors.affiliation: Aneurin Bevan University Health Board Royal Gwent Hospital, Newport NP20 2UB, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Gateley
authors.affiliation: Cardiff University School of Pharmacy and Pharmaceutical Sciences, Cardiff CF10 3NB, UK.
authors.forename: James C
authors.initials: JC
authors.lastname: Birchall
authors.affiliation: Department of Dermatology and Academic Wound Healing, Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Fabien P
authors.initials: FP
authors.lastname: Blanchet
authors.affiliation: Department of Dermatology and Academic Wound Healing, Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK. Electronic address: piguetv@cardiff.ac.uk.
authors.forename: Vincent
authors.initials: V
authors.lastname: Piguet
mesh_terms: D002460:Cell Line; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007801:Langerhans Cells / Q000821:virology*; D009000:Monocytes / Q000378:metabolism; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D064547:Myxovirus Resistance Proteins / Q000378:metabolism; D000076106:SAM Domain and HD Domain-Containing Protein 1; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology
chemical_list: D064547:Myxovirus Resistance Proteins; D016211:Transforming Growth Factor alpha; D016212:Transforming Growth Factor beta; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins