The novel dendritic cell receptor Siglec-1 binds sialyllactose moieties on HIV-1 membrane gangliosides, thereby enhancing HIV-1 transinfection.

Exosomes are secreted cellular vesicles that can be internalized by dendritic cells (DCs), contributing to antigen-specific naive CD4 ؉ T-cell activation. Here, we demonstrate that human immunodeficiency virus type 1 (HIV-1) can exploit this exosome antigen-dissemination pathway intrinsic to mature DCs (mDCs) for mediating trans-infection of T lymphocytes. Capture of HIV-1, HIV-1 Gag-enhanced green fluorescent protein (eGFP) virallike particles (VLPs), and exosomes by DCs was up-regulated upon maturation, resulting in localization within a CD81 ؉ compartment. Uptake of VLPs or exosomes could be inhibited by a challenge with either particle, suggesting that the expression of common determinant(s) on VLP or exosome surface is necessary for internalization by mDCs. Capture by mDCs was insensitive to proteolysis but blocked when virus, VLPs, or exosomes were produced from cells treated with sphingolipid biosynthesis inhibitors that modulate the lipid composition of the budding particles. Finally, VLPs and exosomes captured by mDCs were transmitted to T lymphocytes in an envelope glycoproteinindependent manner, underscoring a new potential viral dissemination pathway. IntroductionDendritic cells (DCs) are specialized antigen-presenting cells that orchestrate innate and adaptive immune responses to invading pathogens. Immature DCs located in the peripheral mucosal tissues recognize and capture microbial pathogens, undergo maturation, and traffic to lymphoid tissues, where they induce adaptive immunity through antigen presentation to naive T cells. Although DCs are required to combat viral infections, viruses, including human immunodeficiency virus type 1 (HIV-1), have evolved strategies to evade their antiviral activity. HIV can gain access into DCs via a nonfusogenic endocytic mechanism, evade classical degradation pathways, and establish productive infection of DCinteracting T cells, a well-studied but poorly understood mechanism of HIV trans-infection of CD4 ϩ T cells. [1][2][3] The efficiency of DC-mediated HIV-1 transmission to T cells can be enhanced by maturing DCs in vitro, 2,4,5 although the mechanism underlying this process has not been well defined. 6 Previous studies have associated HIV trans-infection with the binding of the viral envelope glycoprotein (gp120) to C-type lectin receptors (CLR) such as DC-SIGN, trypsin-sensitive CLR, and CD4-independent receptors expressed on the DC surface. 3,7-11 However, we have recently identified an HIV gp120-independent mechanism of viral binding and endocytosis that is up-regulated upon DC maturation, 12 suggesting that HIV-1 might exploit a preexisting cellular pathway of antigen uptake and transmission. Interestingly, previous reports have shown that DCs can endocytose viral-like particles (VLPs) and induce immune responses. 13,14 Likewise, small secreted cellular organelles, termed exosomes, are also internalized by DCs and sorted into an endocytic compartment, stimulating antigenspecific naive CD4 ϩ T-cell activation in vivo. 15,16 On the basis of similarities i...

In healthy blood donors, serological positivity for human cytomegalovirus (HCMV) is associated with an increased proportion of NK cells bearing the CD94/NKG2C NK cell receptor (NKR). The expression of the activating CD94/NKG2C NKR and of the inhibitory CD94/NKG2A NKR was studied in a cohort of 45 aviremic human immunodeficiency virus type 1 (HIV-1)-positive patients receiving highly active antiretroviral therapy. The proportions of NKG2C+ NK cells were significantly increased in HIV-1-positive patients (mean +/- SD, 25.9% +/- 23.0%), compared with those in 31 healthy individuals (mean +/- SD, 16.1% +/- 20.7%). Yet, the association vanished when HCMV serological status was considered in a multivariate regression model. These results support the conclusion that changes in the NKR repertoire in HIV1-positive patients are related to a concomitant HCMV infection.