Interferon-Inducible Mechanism of Dendritic Cell-Mediated HIV-1 Dissemination Is Dependent on Siglec-1/CD169

Abstract

Human immunodeficiency virus type 1 (HIV-1) interactions with myeloid dendritic cells (DCs) can result in virus dissemination to CD4+ T cells via a trans infection pathway dependent on virion incorporation of the host cell derived glycosphingolipid (GSL), GM3. The mechanism of DC-mediated trans infection is extremely efficacious and can result in infection of multiple CD4+ T cells as these cells make exploratory contacts on the DC surface. While it has long been appreciated that activation of DCs with ligands that induce type I IFN signaling pathway dramatically enhances DC-mediated T cell trans infection, the mechanism by which this occurs has remained unclear until now. Here, we demonstrate that the type I IFN-inducible Siglec-1, CD169, is the DC receptor that captures HIV in a GM3-dependent manner. Selective downregulation of CD169 expression, neutralizing CD169 function, or depletion of GSLs from virions, abrogated DC-mediated HIV-1 capture and trans infection, while exogenous expression of CD169 in receptor-naïve cells rescued GSL-dependent capture and trans infection. HIV-1 particles co-localized with CD169 on DC surface immediately following capture and subsequently within non-lysosomal compartments that redistributed to the DC – T cell infectious synapses upon initiation of T cell contact. Together, these findings describe a novel mechanism of pathogen parasitization of host encoded cellular recognition machinery (GM3 – CD169 interaction) for DC-dependent HIV dissemination.

Cell-Free versus Cell-to-Cell Infection by Human Immunodeficiency Virus Type 1 and Human T-Lymphotropic Virus Type 1: Exploring the Link among Viral Source, Viral Trafficking, and Viral Replication

“…However, these studies also highlighted the fact that trans-infection is not per se dependent upon viral component recognition. Indeed, Siglec-1 has also been identified as the receptor for exosomes (131,134). This finding shed light on earlier studies showing that HIV-1 trafficking in infected cells or in mature MDDCs was very similar to that of exosomes (120).…”

“…Transcriptomic analysis of mature MDDCs displaying different abilities to capture and transfer HIV-1 to T cells allowed the identification of Siglec-1 as an important molecule for HIV-1 trans-infection (122). Direct interaction of GM3 with Siglec-1 was further demonstrated (122,131). Siglec-1 colocalizes with HIV-1 in sac-like compartments and accumulates at the infectious synapse when LPS-matured MDDCs are cocultured with T cells (122,132,133), further demonstrating that DC-mediated trans-infection of T cells relies on Siglec-1.…”

Reactivation of Neutralized HIV-1 by Dendritic Cells Is Dependent on the Epitope Bound by the Antibody

“…The majority of captured HIV-1 by LPS-matured DCs is Env independent, and binding of HIV-1 occurs via a viral membraneincorporated ganglioside interaction with the cellular Siglec-1 receptor (23)(24)(25). HIV-1 captured by these mDCs end up in a CD81-containing compartment where the virus is protected from degradation.…”

“…In contrast, LPS-matured DCs (mDCs) capture HIV-1 predominantly with Siglec-1/CD169, which interacts with sialyllactose-containing gangliosides embedded in the membrane of the virion (23)(24)(25). iDCs can also capture HIV-1 via Siglec-1; however, because of the lower expression of this receptor and the higher expression of C-type lectin receptors, such as DC-SIGN, virus capture is primarily Env dependent.…”

Neutralizing IgG at the Portal of Infection Mediates Protection against Vaginal Simian/Human Immunodeficiency Virus Challenge

“…Another potential pathway of HIV-1 transmission is through DC-mediated trans-infection of CD4 T cells. Here, the C-type lectin receptor DC-SIGN and the sialic acid-binding Ig-like lectin 1 (Siglec-1) contribute to HIV-1 capture in immature DCs (45,46), while in mature DCs capture of virus is independent of DC-SIGN but requires Siglec-1 (46,47). After antigen uptake, DCs become activated and are thought to migrate from submucosal tissue to the draining lymph nodes, where they present virus in trans to CD4 ϩ T cells through virolog- ical synapses (45).…”