Innate Sensing of HIV-1 by Dendritic Cell-Specific ICAM-3 Grabbing Nonintegrin on Dendritic Cells: Degradation and Presentation Versus Transmission of Virus to T Cells Is Determined by Glycan Composition of Viral Envelope

The only exposed protein on the surface of HIV-1, the envelope glycoprotein (env), is a molecular machine that holds the key features required to establish a productive infection by engaging CD4 and coreceptors CCR5/CXCR4. There is growing evidence that env plays a major role in the viral capture, transmission, and dissemination during early stages of HIV-1 infection by hijacking the natural functions of the cells of innate immune system such as Langerhans cells, dendritic cells (DCs), and macrophages. These are strategically located at all the entry sites epidermis, mucosa, lymphoid, and circulatory system to facilitate optimal interaction of the virus during sexual transmission, which is the most common cause of HIV infection.

The enigmatic features of these innate cell interactions with env are mediated primarily by the pattern recognition receptors of membrane-bound c-type lectin receptor (CLRs) family such as Langerin, DC immunoreceptor, DC-specific ICAM-3 grabbing nonintegrin (DC-SIGN), mannose receptor, blood DC antigen 2, and Sialic acid-binding immunoglobulin-type lectins (SIGLEC-1), the most important CLRs that recognize exclusively the glycans on the surface of HIV-1 env. ¹ The innate cells and the CLRs they express are spatially and temporally distributed along the sexual transmission pathway to generally form the first line of defense and perform differential functions leading finally to viral internalization and endosomal degradation for efficient antigen presentation, and also modulate toll like receptor (TLR)-induced cytokine expression to enhance the infection of HIV.

The fate of virus being taken up by these cells, whether shuttled to the endocytic pathway leading to degradation and presentation or transmission pathway by trafficking to a tetraspanin (CD81)-enriched protective environment, is not known. ^2,3 The env glycans serve as pathogen-associated molecular pattern and it is the sole target of CLRs. The role of env glycans in the determination of fate of virus within DCs has been determined by altering the glycan composition of the virus envelope into more homogeneous glycans by producing viruses under different glycosylation inhibitory conditions using glycosylation pathway inhibitors, swainsonine (Golgi mannosidase II inhibitor), kifunensine (ER mannosidase I inhibitor), and GnTI^−/− (GlcNAc transferase I) mutant cell line (293S). Using this strategy, it has been shown that viral glycan heterogeneity affects the binding of virus to DC-SIGN receptor. ⁴ Viruses with more homogeneous glycans and higher oligomannose content especially GlcNAc₂Man₉ bound more tightly to DC-SIGN followed by viruses with higher content of GlcNAc₂Man₅ than viruses with heterogeneous glycans. The glycan composition was further shown to affect the transfer of virus to T cells and was found that viruses with more homogeneous glycans and higher oligomannose content were transmitted less efficiently than viruses with heterogeneous glycans. The viruses with more homogeneous glycans and higher oligomannose content colocalized more within endocytic compartment, whereas the virus with heterogeneous glycans colocalized within CD81 compartments. Determination of the relative degradation of the glycan-altered viruses, it was found that viruses with more oligomannose content degrade faster than those with heterogeneous glycans. ⁴ We also found similar results using tier 1 SF162.LS, tier 2 chronic (JRFL.JB) and acute (REJO4541.67), and tier 3 (PVO.4) viruses using RAJI cell line as well as monocyte-derived DCs. Together, these findings are consistent with the previous study ⁴ and confirm that glycan composition regulates the fate of virus, either to antigen presentation or to transmission pathway. The different modes of DC-SIGN-mediated effector functions toward HIV are summarized in Figure 1, with special emphases on glycan composition, which regulates the pathway taken within DCs by HIV-1 through DC-SIGN.

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FIG. 1.

Recognition of HIV-1 by the innate immune system through CLRs expressed by different subtypes of DCs and macrophages lining the sexual route of HIV-1 transmission, and their role in viral dissemination. These cells commonly work as professional APCs and express both primary receptors of HIV-1 infection, CD4, and coreceptors CCR5/CXCR4, as well as innate PRRs such as CLRs. The viruses may enter DCs through primary receptors and cause infection, called cis-infection (1) and function as reservoirs of virus. The mucosal DCs express DC-SIGN, a well-studied CLR, which has very high affinity for the mannose glycans extensively present on the HIV-1 envelope. The DC-SIGN captures the virus, and fate of virus within the cell has been shown to follow many pathways, which ultimately lead to either degradation and presentation of virus to T cells (3A) or transmission and dissemination of virus within the host (3B). We and other studies provide evidence that the fate of virus for either of the pathways is determined by the glycan composition of the env of the virus. The virus being captured on DC-SIGN may be presented directly to T cells called transinfection (2) or may be endocytosed (3). The fate of endocytosed virus within the cell is determined by the envelope glycan composition of the virus. Viruses with homogeneous glycan of high mannose Man5-9GlcNAc2 type and absence of complex glycans bind strongly to high mannose recognizing receptor DC-SIGN and possibly to other mannose-dependent CLRs, rendering their release and transfer to other cells unlikely. These viruses are taken up through lysosomal degradation pathway (3A) to present the viral antigens through MHC II to TCR (4). Viruses with complex mixture of heterogeneous glycans bind to DC-SIGN with relatively lower avidity and make it possible for the virus to be released from the receptor and transferred directly through transinfection. Within the cell, the viruses with heterogeneous glycans are preserved within the CD81-endosomal compartments (3B) to prevent degradation and preserve the insidious reservoir of viral particles. The infectious viruses along with MVBs are transferred to T cells (5) or the virus is recycled along with or without DC-SIGN to the cell surface and transferred to T cells through transinfection or free virus particles (6). The DC-SIGN further activates a signal transduction pathway that activates through TLR7/TLR8, the genes that enhance the infection of the cells (7). The numbers in this legend refer to the pathway number in the figure. APCs, antigen presenting cells; CLR, C-type lectin receptor; DC, dendritic cell; DC-SIGN, dendritic cell-specific ICAM-3 grabbing nonintegrin; MHC, major histocompatibility complex; MVBs, multivesicular bodies; PRRs, pattern recognition receptors; TCR, T-cell receptor; TLR, toll like receptor. Color image is available online at www.liebertpub.com/aid