title: CD169-mediated trafficking of HIV to plasma membrane invaginations in dendritic cells attenuates efficacy of anti-gp120 broadly neutralizing antibodies.
abstract: 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.
authors.affiliation: Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Akiyama
authors.affiliation: Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Nora-Guadalupe Pina
authors.initials: NG
authors.lastname: Ramirez
authors.affiliation: Bruker Nano Surfaces, Salt Lake City, Utah, United States of America.
authors.forename: Manasa V
authors.initials: MV
authors.lastname: Gudheti
authors.affiliation: Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Suryaram
authors.initials: S
authors.lastname: Gummuluru
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D004591:Electrophoresis, Polyacrylamide Gel; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D057131:Immune Evasion / Q000276:immunology*; D008854:Microscopy, Electron; D063267:Sialic Acid Binding Ig-like Lectin 1 / Q000276:immunology* / Q000378:metabolism; D016662:Virus Integration
chemical_list: D057134:Antibodies, Neutralizing; D015699:HIV Envelope Protein gp120; C571166:SIGLEC1 protein, human; D063267:Sialic Acid Binding Ig-like Lectin 1