Sialyllactose in Viral Membrane Gangliosides Is a Novel Molecular Recognition Pattern for Mature Dendritic Cell Capture of HIV-1

Altres ajudes: "Gala contra la sida: Barcelona 2011"; programa HIVACAT; programa José Castillejo del Ministerio de Cultura y DeporteAn accessible sialyllactose moiety on viral membrane gangliosides is shown to be essential for HIV-1 uptake into mature dendritic cells, thereby promoting viral transfer and infection of bystander CD4+ T lymphocytes. HIV-1 is internalized into mature dendritic cells (mDCs) via an as yet undefined mechanism with subsequent transfer of stored, infectious virus to CD4 + T lymphocytes. Thus, HIV-1 subverts a DC antigen capture mechanism to promote viral spread. Here, we show that gangliosides in the HIV-1 membrane are the key molecules for mDC uptake. HIV-1 virus-like particles and liposomes mimicking the HIV-1 lipid composition were shown to use a common internalization pathway and the same trafficking route within mDCs. Hence, these results demonstrate that gangliosides can act as viral attachment factors, in addition to their well known function as cellular receptors for certain viruses. Furthermore, the sialyllactose molecule present in specific gangliosides was identified as the determinant moiety for mDC HIV-1 uptake. Thus, sialyllactose represents a novel molecular recognition pattern for mDC capture, and may be crucial both for antigen presentation leading to immunity against pathogens and for succumbing to subversion by HIV-1. Antigen-presenting cells such as dendritic cells (DCs) are required to combat infections, but viruses including HIV have evolved strategies to evade their anti-viral activity. HIV can enter DCs via a non-infectious endocytic mechanism and trick them into passing infectious virus on to bystander CD4 + T cells. Immature DC (iDCs) are characterized by high endocytic activity and low T-cell activation potential. Interestingly, several groups have shown that DCs that have undergone "'maturation'" (mDCs), a process that occurs on contact with a presentable antigen, capture higher numbers of HIV-1 particles than iDCs when they are matured in the presence of lipopolysaccharide. mDCs move to the lymph nodes where they have more opportunity to interact with T cells than iDCs, and thus to pass on infectious virus. But the molecular mechanism underlying HIV-1 uptake by mDCs has until now been elusive. Here we show that gangliosides, basic components of the host cell's plasma membrane, have an important role in this process. Gangliosides are known to be incorporated into the viral envelope membrane during the process of viral particle budding and here we show that they serve as viral attachment factors: they are recognized and enable HIV-1 uptake by mDCs. Thus, in addition to the well-known function of gangliosides as host cell receptors that mediate virus (e.g., polyoma and SV40) attachment and transport from the plasma membrane to the ER, we now demonstrate that they can also act as determinants for capture by mDCs. Furthermore, we identify a moiety composed of sialyllactose on HIV-1 membrane gangliosides as the specific domain recognized by mDCs. We propose that this novel recognition moiety might be crucial for inducing immune responses, but also critical to disseminate HIV-1 and other ganglioside-containing viruses