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.
Highlights
Myeloid dendritic cells (DCs) are professional antigen presenting cells that play sentinel roles in sensing pathogens and priming adaptive immunity [1]
We report that a myeloid cell specific co-factor interacts with CD169—HIV-1 interaction is a protein (CD169) following virus capture leading to compartment formation
Though the CD169+ HIV-1 containing compartments are surface-accessible, these compartments have considerable depth and are connected to the surface, such that captured virus particles localized within these unique structures are protected from detection by anti-gp120 broadly neutralizing antibodies
Summary
Myeloid dendritic cells (DCs) are professional antigen presenting cells that play sentinel roles in sensing pathogens and priming adaptive immunity [1]. While DCs are infected with HIV and DC-derived progeny viruses can infect CD4+ T cells [4,5,6,7], productive infection of DCs is limiting for several reasons including low receptor/co-receptor density, presence of cell-intrinsic restriction factors and innate sensing mechanisms eliciting anti-virus immune responses such as type I interferon secretion [8,9,10,11]. Upon HIV-1 binding to CD169 on mature DCs, HIV-1 particles accumulate in CD81 tetraspanin+ compartments [13,14] These compartments are, only weakly or poorly stained with endosome/lysosome markers such as CD63 and Lamp1 [16,17]. How CD169-bound HIV-1 particles are accumulated and viral infectivity preserved in these compartments remains unclear
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