OK so this is the first #microtwjc of the new year (yay!) and I would like to kick off the year with an important paper that appeared in PLoS Biology a couple of weeks back that investigated how the HIV virus is able to coax some of your own immune cells to help it infect another class of immune cells: your T cells. They focus on a kind of molecule known as a lectin (SIGLEC-1) that binds to HIV particles and can facilitate this process (I’ll write a more in-depth analysis of the work later but for now that’s all you need to know). This is a very important mechanism in HIV infection, disease and transmission and this paper could facilitate the development of drugs to target the molecule. Either way it’s a very nice, relatively simple paper. It also supersedes previous evidence implicating another molecule known as DC-SIGN in doing essentially the same thing. (Isn’t science fun?).

 

Siglec-1 Is a Novel Dendritic Cell Receptor That Mediates HIV-1 Trans-Infection Through Recognition of Viral Membrane Gangliosides

Izquierdo-Useros N et al 2012.

 

 Abstract:

Dendritic cells (DCs) are essential antigen-presenting cells for the induction of immunity against pathogens. However, HIV-1 spread is strongly enhanced in clusters of DCs and CD4+T cells. Uninfected DCs capture HIV-1 and mediate viral transfer to bystander CD4+ T cells through a process termed trans-infection. Initial studies identified the C-type lectin DC-SIGN as the HIV-1 binding factor on DCs, which interacts with the viral envelope glycoproteins. Upon DC maturation, however, DC-SIGN is down-regulated, while HIV-1 capture and trans-infection is strongly enhanced via a glycoprotein-independent capture pathway that recognizes sialyllactose-containing membrane gangliosides. Here we show that the sialic acid-binding Ig-like lectin 1 (Siglec-1, CD169), which is highly expressed on mature DCs, specifically binds HIV-1 and vesicles carrying sialyllactose. Furthermore, Siglec-1 is essential for trans-infection by mature DCs. These findings identify Siglec-1 as a key factor for HIV-1 spread via infectious DC/T-cell synapses, highlighting a novel mechanism that mediates HIV-1 dissemination in activated tissues.

 Author summary:

Mature dendritic cells (mDCs) capture and store infectious HIV-1 and subsequently infect neighboring CD4+ T cells in lymphoid organs. This process, known as trans-infection, is a key contributor to HIV pathogenesis, but the precise mechanism and the identity of the receptor on the mDC surface that recognizes viral particles remain controversial. Although the interaction of HIV-1 envelope glycoproteins with the C-type lectin DC-SIGN has been suggested to mediate HIV-1 capture and trans-infection, later studies revealed an envelope glycoprotein-independent virus capture mechanism in mDCs. Here, we identify Siglec-1 as the surface receptor on mDCs that boosts their uptake of HIV-1 and their capacity to trans-infect CD4+cells, leading in turn to HIV-1 disease progression. Siglec-1 captures the virus by interacting with sialyllactose-containing gangliosides exposed on viral membranes. This indicates that Siglec-1 functions as a general binding molecule for any vesicle carrying sialyllactose in its membrane, including exosomes and other viruses. We suggest that this natural pathway through mDC, which would normally lead to antigen processing and presentation, has been subverted by HIV-1 for its own storage and transmission.

 Discussion points:

  • Is it convincing evidence to say that SIGLEC-1 is the mediator of HIV trans-infection? What other evidence would you want to see?

 

  • Why is their a difference to classical cell entry receptors for HIV and cell-binding receptors like SIGLEC-1?

 

  • Could you/should you target this molecule?

 

  • What does it mean for HIV infection and disease? Remember it is an LPS-upregulated molecule and could be implicated in co-infections with mycobacteria.

 

  • What does it mean for HIV evolution/emergence? Do you think chimpanzee SIGLEC-1 is much different? Is this a reason why HIV could spillover?

 

Further reading:

 

 

 

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