Dendritic Cells From the Cervical Mucosa Capture and Transfer HIV-1 via Siglec-1

Abstract

Antigen presenting cells from the cervical mucosa are thought to amplify incoming HIV-1 and spread infection systemically without being productively infected. Yet, the molecular mechanism at the cervical mucosa underlying this viral transmission pathway remains unknown. Here we identified a subset of HLA-DR + CD14 + CD11c + cervical DCs at the lamina propria of the ectocervix and the endocervix that expressed the type-I interferon inducible lectin Siglec-1 (CD169), which promoted viral uptake. In the cervical biopsy of a viremic HIV-1 + patient, Siglec-1 + cells harbored HIV-1-containing compartments, demonstrating that in vivo , these cells trap viruses . Ex vivo , a type-I interferon antiviral environment enhanced viral capture and trans -infection via Siglec-1. Nonetheless, HIV-1 transfer via cervical DCs was effectively prevented with antibodies against Siglec-1. Our findings contribute to decipher how cervical DCs may boost HIV-1 replication and promote systemic viral spread from the cervical mucosa, and highlight the importance of including inhibitors against Siglec-1 in microbicidal strategies.

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

“…Although increased antiviral IFNα secretion could limit initial viral infection, it could promote viral capture on cervical myeloid cells via Siglec-1 induction as well. Of note, in the cervical biopsy of a viremic HIV-1 + patient, Siglec-1 + cells harbored HIV-1-containing compartments, demonstrating that in vivo, these cells can trap viruses [56]. Interestingly, similar VCC-like structures have been detected in urethral macrophages of HIV-1-infected individuals under suppressive combination antiretroviral therapy [144], but if Siglec-1 is implicated in the formation of these particular structures remains to be determined.…”

“…Of note, pDC activation in response to HIV-1 sensing induces IFNα secretion through Toll-like receptor (TLR) -7 and -9 signaling [47,53] and maturation of bystander myeloid DCs [54], and this IFNα response is more potent on pDCs derived from females [55]. In turn, secretion of this cytokine can directly upregulate Siglec-1 expression on DCs [56] ( Figure 1A).…”

“…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].…”

“…Recently, we have identified the presence of Siglec-1-expressing cells in cervical mucosa. These DCs are capable of capturing HIV-1 and mediate viral transmission to target CD4 + cells via trans-infection, even in a basal state where no apparent activation is detected [56] (Figure 4). Indeed, DCs directly isolated from human ectocervix displayed a basal Siglec-1 expression that was sufficient to mediate viral transfer.…”

Siglecs at the Host–Pathogen Interface

“…Host cellderived α2,3 sialylated glycosphingolipid (GSL) on the HIV-1 particle membrane is the ligand for Siglec-1 on mDC required for triggering mDC-mediated transinfection of CD4 + T cells in lymphoid organs (Yu et al 2014;Izquierdo-Useros et al 2012;Puryear et al 2013). A population of cervical DCs at the lamina propria of the ectocervix and the endocervix that express Siglec-1 may be particularly important, and ex vivo studies suggest that CD4 + T cell trans-infection from these cells can be blocked by addition of anti-Siglec-1 antibodies (Perez-Zsolt et al 2019a).…”