Inhibition of Two Temporal Phases of HIV-1 Transfer from Primary Langerhans Cells to T Cells: The Role of Langerin

Abstract

Epidermal Langerhans cells (eLCs) uniquely express the C-type lectin receptor langerin in addition to the HIV entry receptors CD4 and CCR5. They are among the first target cells to encounter HIV in the anogenital stratified squamous mucosa during sexual transmission. Previous reports on the mechanism of HIV transfer to T cells and the role of langerin have been contradictory. In this study, we examined HIV replication and langerin-mediated viral transfer by authentic immature eLCs and model Mutz-3 LCs. eLCs were productively infected with HIV, whereas Mutz-3 LCs were not susceptible because of a lack of CCR5 expression. Two successive phases of HIV viral transfer to T cells via cave/vesicular trafficking and de novo replication were observed with eLCs as previously described in monocyte-derived or blood dendritic cells, but only first phase transfer was observed with Mutz-3 LCs. Langerin was expressed as trimers after cross-linking on the cell surface of Mutz-3 LCs and in this form preferentially bound HIV envelope protein gp140 and whole HIV particles via the carbohydrate recognition domain (CRD). Both phases of HIV transfer from eLCs to T cells were inhibited when eLCs were pretreated with a mAb to langerin CRD or when HIV was pretreated with a soluble langerin trimeric extracellular domain or by a CRD homolog. However, the langerin homolog did not inhibit direct HIV infection of T cells. These two novel soluble langerin inhibitors could be developed to prevent HIV uptake, infection, and subsequent transfer to T cells during early stages of infection.

Herpes Simplex Virus Type 2–Infected Dendritic Cells Produce TNF-α, Which Enhances CCR5 Expression and Stimulates HIV Production from Adjacent Infected Cells

“…The application of TNF-a-containing supernatants would be expected to induce partial MDDC maturation and delay the degradation of HIV p24 Ag in virus-containing compartments, which could confound using this test as a measure of de novo HIV replication. However, this was anticipated by performing the intracellular p24 Ag assays at 96 hpi, long after such Ag has decayed to negligible levels in mature MDDCs, as previously shown with much more potent inducing stimuli (40).…”

“…An alternative explanation could be enhanced persistence of the HIV inoculum, but we and others have previously shown this is degraded in MDDCs by 24 hpi. Therefore, p24ag present in MDDCs after 48 hpi represents de novo replication as shown by AZT inhibition (31,40,41). Furthermore, enhanced persistence of HIV inoculum would not explain the increase in HIV cDNA.…”

Narcolepsy risk loci are enriched in immune cells and suggest autoimmune modulation of the T cell receptor repertoire

“…Increased T1N incidence following the Pandemrix® vaccination was 15 first seen in Northern Europe [13][14][15][16][17][18][19][20] with 8-fold increase in incidence in (0.79/100,000 to 16 6.3/100,000) in children. The specificity was striking, as increased T1N was later detected in all 17 countries where Pandemrix® was used, whereas countries using other pH1N1 vaccine brands 18 did not detect vaccination-associated increases in incidence [13][14][15][16][17][18][19][20][21][22] . is defined by antigen presentation, mediated through specific T cell receptor chains, and 27 modulated by influenza-A as a critical trigger.…”

The C-type Lectin Langerin Functions as a Receptor for Attachment and Infectious Entry of Influenza A Virus

“…Human immunodeficiency virus type 1(HIV-1) is recognized by a variety of CLRs, including DC-SIGN, MMR, and langerin (18,19). While initial studies suggested that recognition by langerin resulted in uptake and degradation of HIV-1 in Birbeck granules (20), recent studies show that langerin-mediated uptake can facilitate transfer of the virus from DC to T cells, in a manner analogous to that reported for DC-SIGN (21)(22)(23)(24)(25). This occurs via two routes, either via plasma membrane-linked (neutral pH) intracellular compartments or via receptors for enhanced de novo replication in DC, thus facilitating virus transmission.…”