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.
Highlights
Human immunodeficiency virus type 1 (HIV-1) infection of macrophages and T cells requires both CD4 and chemokine receptors [1]
Conclusions and Significance of the Findings: Our study showed that sialic acids on the viral envelope facilitated HIV-1 infection of macrophages through interacting with Sialic acid-binding immunoglobulin-like lectins (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
Summary
Human immunodeficiency virus type 1 (HIV-1) infection of macrophages and T cells requires both CD4 and chemokine receptors [1]. While binding to CD4 provides mainly viral attachment to host cells, the interaction of the viral envelope protein gp120 with chemokine receptors initiates conformational changes leading to the fusion and entry of the virus [2]. Unlike CD4+ T cells, macrophages express relatively low levels of CD4 thereby complicating efficient viral entry [6]. Additional attachment factors, including carbohydrate receptors, have been proposed to facilitate infection of macrophages [7]. Human immunodeficiency virus type 1 (HIV-1) infects macrophages effectively, despite relatively low levels of cell surface-expressed CD4. 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
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