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Review
. 2017 Mar 23:8:314.
doi: 10.3389/fimmu.2017.00314. eCollection 2017.

Host Immune Responses in HIV-1 Infection: The Emerging Pathogenic Role of Siglecs and Their Clinical Correlates

Joanna Mikulak  1 , Clara Di Vito  2 , Elisa Zaghi  2 , Domenico Mavilio  3
Affiliations
Review

Host Immune Responses in HIV-1 Infection: The Emerging Pathogenic Role of Siglecs and Their Clinical Correlates

Joanna Mikulak et al. Front Immunol. .

Abstract

A better understanding of the mechanisms employed by HIV-1 to escape immune responses still represents one of the major tasks required for the development of novel therapeutic approaches targeting a disease still lacking a definitive cure. Host innate immune responses against HIV-1 are key in the early phases of the infection as they could prevent the development and the establishment of two hallmarks of the infection: chronic inflammation and viral reservoirs. Sialic acid-binding immunoglobulin-like lectins (Siglecs) belong to a family of transmembrane proteins able to dampen host immune responses and set appropriate immune activation thresholds upon ligation with their natural ligands, the sialylated carbohydrates. This immune-modulatory function is also targeted by many pathogens that have evolved to express sialic acids on their surface in order to escape host immune responses. HIV-1 envelope glycoprotein 120 (gp120) is extensively covered by carbohydrates playing active roles in life cycle of the virus. Indeed, besides forming a protecting shield from antibody recognition, this coat of N-linked glycans interferes with the folding of viral glycoproteins and enhances virus infectivity. In particular, the sialic acid residues present on gp120 can bind Siglec-7 on natural killer and monocytes/macrophages and Siglec-1 on monocytes/macrophages and dendritic cells. The interactions between these two members of the Siglec family and the sialylated glycans present on HIV-1 envelope either induce or increase HIV-1 entry in conventional and unconventional target cells, thus contributing to viral dissemination and disease progression. In this review, we address the impact of Siglecs in the pathogenesis of HIV-1 infection and discuss how they could be employed as clinic and therapeutic targets.

Keywords: NK cells; dendritic cells; host-pathogen interactions; monocytes/macrophages.

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Figures

Figure 1
Figure 1
Siglecs in the pathogenesis and clinical outcomes of HIV-1 infection. (A) Chronic HIV-1 infection leads to the downregulation of Siglec-7 expression on natural killer (NK) cells and increases plasma levels of its soluble form of Siglec-7 (sSiglec-7). (B) Moreover, HIV-1 monocytes/macrophages induces higher expressions of Siglec-1, CD4, and chemokine co-receptors (CCR5 and CXCR4) on monocytes and macrophages, while do not affects the constitutive high surface levels of Siglec-7 on the same cells. Siglec-1 is also expressed on mature dendritic cells (mDCs), monocytes, and macrophages, and high levels of HIV-1 viremia increase even more its surface expression on the latter two cell types. Due to their distribution on immune cells and to their ability to bind the viral envelope glycoprotein 120 heavily conjugated with sialic acids residues, Siglec-7 and Siglec-1 are highly relevant in the pathogenesis of HIV-1 infection. Indeed, after the binding of HIV-1 to Siglec-1, both mDCs and monocytes/macrophages retain virions with different mechanisms, a phenomenon enhancing the HIV-1 infection of CD4pos lymphocytes. Moreover, the HIV-1 uptake by Siglec-1 and Siglec-7 further contribute to the spreading of infection by using both DCs and monocyte/macrophages as cellular-infected carriers of the virus. The shedding of Siglec-7 from NK cells in the presence of high levels of HIV-1 viremia also significantly increases HIV-1 viral entry in Siglec-7neg/CD4pos T cells. Finally, the engagement of Siglec-7 on monocytes and macrophages promotes cellular activation in monocytes and macrophages and contributes to the establishment of persistent inflammation in HIV-1-infected patients. These abnormalities in Siglec phenotype and functions in HIV-1 infection can be used as clinical tools to monitor disease progression or can be targeted to develop innovative therapeutic approaches to limit viral spreading and disease progression.
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