Constitutive Siglec-1 expression confers susceptibility to HIV-1 infection of human dendritic cell precursors

Abstract

The human dendritic cell (DC) lineage has recently been unraveled by high-dimensional mapping, revealing the existence of a discrete new population of blood circulating DC precursors (pre-DCs). Whether this new DC population possesses specific functional features as compared to the other blood DC subset upon pathogen encounter remained to be evaluated. A unique feature of pre-DCs among blood DCs is their constitutive expression of the viral adhesion receptor Siglec-1. Here, we show that pre-DCs, but not other blood DC subsets, are susceptible to infection by HIV-1 in a Siglec-1–dependent manner. Siglec-1 mediates pre-DC infection of CCR5- and CXCR4-tropic strains. Infection of pre-DCs is further enhanced in the presence of HIV-2/SIVmac Vpx, indicating that Siglec-1 does not counteract restriction factors such as SAMHD1. Instead, Siglec-1 promotes attachment and fusion of viral particles. HIV-1–infected pre-DCs produce new infectious viral particles that accumulate in intracellular compartments reminiscent of the virus-containing compartment of macrophages. Pre-DC activation by toll-like receptor (TLR) ligands induces an antiviral state that inhibits HIV-1 fusion and infection, but Siglec-1 remains functional and mediates replication-independent transfer of HIV-1 to activated primary T lymphocytes. Altogether, Siglec-1–mediated susceptibility to HIV-1 infection of pre-DCs constitutes a unique functional feature that might represent a preferential relationship of this emerging cell type with viruses.

When Dendritic Cells Go Viral: The Role of Siglec-1 in Host Defense and Dissemination of Enveloped Viruses

“…Viral sensing enhances Siglec-1 expression on APCs, and this facilitates HIV-1 infection of DCs and other myeloid cells (Figure 2A, top), such as macrophages [81]. Although DCs are generally resistant to HIV-1 infection, a recent study showed that Siglec-1 mediated HIV-1 productive infection of a population of human DC precursors known as pre-DCs [82]. Even though all DCs express the HIV-1-interacting cellular receptor CD4 and the viral coreceptors [83,84], being therefore susceptible to viral infection in vitro [85][86][87], infectivity was less prominent than in activated CD4 + T cells [88][89][90][91].…”

“…Thus, trapped viruses are efficiently transmitted across infectious synapses to susceptible lymphocytes [9,132,133] ( Figure 3). This mechanism of viral transmission is known as trans-infection [134] and is mediated by Siglec-1 on activated monocyte-derived DCs, monocytes, blood conventional DCs, pre-DCs, and primary myeloid cells isolated from lymphoid and cervical tissues [38][39][40]56,63,82].…”

A human circulating immune cell landscape in aging and COVID-19

“…In human peripheral blood myeloid cells (including MCs and DCs), known to promote antigen presentation and inflammatory activities, we identified seven transcriptionally distinct subsets: (Fig. S3N), and dendritic cell precursors (pre-DCs) expressing AXL and CD123 (Grabiec and Hussell, 2016;Ruffin et al, 2019) (Fig. S3N).…”

Perturbations in the mononuclear phagocyte landscape associated with COVID-19 disease severity

“…In the present study, elevated levels of CD147 on iMonos and ncMonos was a general feature of all patients, while increased levels of CD147 on pDCs, pre-DCs and pre-DC2s were specific to severe COVID-19. In this context it is interesting to note that DC progenitors can themselves be susceptible to viral insult 50 . It remains to be addressed what causes CD147 upregulation in COVID-19 and how the MNP system may participate in dysregulated coagulation, but it has previously been shown that CD147 support platelet-monocyte interactions promoting vascular inflammation 51 .…”