Siglecs Facilitate HIV-1 Infection of Macrophages through Adhesion with Viral Sialic Acids

Abstract

BackgroundHuman immunodeficiency virus type 1 (HIV-1) infects macrophages effectively, despite relatively low levels of cell surface-expressed CD4. Although HIV-1 infections are defined by viral tropisms according to chemokine receptor usage (R5 and X4), variations in infection are common within both R5- and X4-tropic viruses, indicating additional factors may contribute to viral tropism.Methodology and Principal FindingsUsing both solution and cell surface binding experiments, we showed that R5- and X4-tropic HIV-1 gp120 proteins recognized a family of I-type lectin receptors, the Sialic acid-binding immunoglobulin-like lectins (Siglec). The recognition was through envelope-associated sialic acids that promoted viral adhesion to macrophages. The sialic acid-mediated viral-host interaction facilitated both R5-tropic pseudovirus and HIV-1BaL infection of macrophages. The high affinity Siglec-1 contributed the most to HIV-1 infection and the variation in Siglec-1 expression on primary macrophages from different donors was associated statistically with sialic acid-facilitated viral infection. Furthermore, envelope-associated sialoglycan variations on various strains of R5-tropic viruses also affected infection.Conclusions and Significance of the FindingsOur study showed that sialic acids on the viral envelope facilitated HIV-1 infection of macrophages through interacting with Siglec receptors, and the expression of Siglec-1 correlated with viral sialic acid-mediated host attachment. This glycan-mediated viral adhesion underscores the importance of viral sialic acids in HIV infection and pathogenesis, and suggests a novel class of antiviral compounds targeting Siglec receptors.

Siglec1 suppresses antiviral innate immune response by inducing TBK1 degradation via the ubiquitin ligase TRIM27

“…Several types of pathogens can exploit sialic acids, which are either synthesized by themselves or acquired from the host, to activate inhibitory Siglecs on innate immune cells, thus attenuating host protective responses and achieving immune evasion [11]. Membrane Siglec1 has been reported to be utilized by HIV-1 to infect macrophages [29]. Together with our data that Siglec1 expression was upregulated upon viral infection, we thus speculate that Siglec1 upregulation may be an important and common strategy utilized by different families of viruses to evade host immune responses.…”

Siglec-mediated regulation of immune cell function in disease

“…A key question to be addressed is whether this pathway has an important role in HIV infection and spread in vivo since sialoadhesin is not normally expressed on DCs but is restricted to subsets of inflammatory monocytes and tissue macrophages 21 . In this regard, HIV can also interact with other Siglecs, including Siglec-3, Siglec-5, Siglec-7 and Siglec-9 via sialylated gp120, also promoting infection of macrophages 46 …”

The role of Siglec-1 in HIV-1/macrophage interaction

“…In DCs, Siglec-1 serves as a receptor for capturing HIV-1 through its Ig-like V set domain by binding to host-derived glycosphingolipid (ganglioside GM3) that is incorporated in the membrane of HIV-1 particles. This interaction between Siglec-1 and GM3 is independent of the HIV envelope protein [22] , while in macrophages the capture of HIV-1 is through the interaction of Siglec-1 and HIV-1 envelope protein [15,16] . Studies have shown that Siglec-1 expression is influenced by the cytokines present in the environmental milieu induced as a result of chronic inflammation [23,24] .…”

“…However, unlike CD4+ T cells, macrophages and monocyte-derived macrophages express relatively low levels of CD4 on the cell surface further confounding the role of this molecule in HIV-1 entry into macrophages. Recently, the role of sialic acid-binding immunoglobulin-like lectin-1 (Siglec-1) in HIV-1 infection of myeloid cells has been investigated, and shown to play an important role in HIV-1 pathogenesis in both dendritic cells [13,14] and macrophages [15,16] . This highlight will focus on (i) the effect of environmental milieu on Siglec-1 expression on macrophages, (ii) the role of Siglec-1 in HIV-1 infection of macrophages, and (iii) the interaction of Siglec-1 with the virus envelope.…”