CD169-mediated trafficking of HIV to plasma membrane invaginations in dendritic cells attenuates efficacy of anti-gp120 broadly neutralizing antibodies

• Published in: PLoS pathogens 2015-03, Vol.11 (3), p.e1004751-e1004751
• Main Authors: Akiyama, Hisashi, Ramirez, Nora-Guadalupe Pina, Gudheti, Manasa V, Gummuluru, Suryaram
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; AIDS; Antibodies; Antibodies, Neutralizing - immunology; Cell Membrane - immunology; Cell Membrane - metabolism; Cell membranes; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dendritic Cells - virology; Electrophoresis, Polyacrylamide Gel; Health aspects; HIV; HIV Envelope Protein gp120 - immunology; HIV Infections - immunology; HIV-1 - immunology; Host-virus relationships; Humans; Identification and classification; Immune Evasion - immunology; Infections; Ligands; Lymphocytes; Microscopy; Microscopy, Electron; Plasma; Rodents; Sialic Acid Binding Ig-like Lectin 1 - immunology; Sialic Acid Binding Ig-like Lectin 1 - metabolism; Virus Integration
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1004751

Myeloid dendritic cells (DCs) can capture HIV-1 via the receptor CD169/Siglec-1 that binds to the ganglioside, GM3, in the virus particle membrane. In turn, HIV-1 particles captured by CD169, an I-type lectin, whose expression on DCs is enhanced upon maturation with LPS, are protected from degradation in CD169+ virus-containing compartments (VCCs) and disseminated to CD4⁺ T cells, a mechanism of DC-mediated HIV-1 trans-infection. In this study, we describe the mechanism of VCC formation and its role in immune evasion mechanisms of HIV-1. We find HIV-1-induced formation of VCCs is restricted to myeloid cells, and that the cytoplasmic tail of CD169 is dispensable for HIV-1 trafficking and retention within VCCs and subsequent trans-infection to CD4⁺ T cells. Interestingly, introduction of a di-aromatic endocytic motif in the cytoplasmic tail of CD169 that results in endocytosis of HIV-1 particles, suppressed CD169-mediated HIV-1 trans-infection. Furthermore, super-resolution microscopy revealed close association of CD169 and HIV-1 particles in surface-accessible but deep plasma membrane invaginations. Intriguingly, HIV-1 particles in deep VCCs were inefficiently accessed by anti-gp120 broadly neutralizing antibodies, VRC01 and NIH45-46 G54W, and thus were less susceptible to neutralization. Our study suggests that HIV-1 capture by CD169 can provide virus evasion from both innate (phagocytosis) and adaptive immune responses.