HIV-1 Gag specifically restricts PI(4,5)P2 and cholesterol mobility in living cells creating a nanodomain platform for virus assembly
Posted on: 11 March 2019
Preprint posted on 11 March 2019
Categories: biochemistry, biophysics, cell biology, microbiology
Background
During the last step of the HIV-1 replication cycle the assembled virus buds from cells before finding its next cell to infect. When the viruses bud off they have a different membrane composition compared to the rest of the cell. The lipids are densely packed and consist mainly of sphingomyelins, cholesterol and phosphoinositides1. But the question remains whether HIV targets these densely packed locations or whether it sequesters the lipids to make it’s self a suitable region on which to assemble, and if so how?
Key findings
The authors use live CD4+ Jurkat cells and a combination of confocal imaging of GFP-labelled Gag proteins (Gag is involved in lipid binding and Gag-multimerising) and scanning stimulated emission depletion microscopy with fluorescence correlation microscopy (sSTED-FCS) to monitor diffusion of ATTO647N labelled lipids at HIV-1 assembly sites.
sSTED-FCS is an interesting technique that scans the same orbit multiple times creating a lipid signal intensity fluctuation carpet which allows determination of the diffusion of molecules. The scanning element of the technique allows mapping of lipid molecules that move at different rates, e.g. those that have arrested movement or those in lipid rafts2. By monitoring the lipid signal at a HIV assembly site and areas outside the assembly site the authors determined there was an 8-10 fold reduction in lipid mobility at the HIV assembly site for PI(4,5)P2 and cholesterol, but not for sphingomyelins or phosphatidylethanolamine. Furthermore, they show that the Gag protein alone is sufficient to sequester PI(4,5)P2 and cholesterol and reduce lipid mobility, however the fold reduction in lipid mobility was only 2.2 fold between inside and outside the HIV-1 assembly sites. Therefore, HIV-1, and Gag in particular, sequesters certain lipids to form its own assembly raft.
Figure 1 and 2 modified from the preprint. Confocal imaging of the location of Gag-GFP identifying the HIV-1 assembly site pre and post sSTED-FCS and lipid localisations during orbital sSTED-FCS imaging. (a+b) PI(4,5)P2 and Chol have a lower diffusion coefficient inside the HIV-1 assembly site (red) compared to outside the site and in uninfected controls (blue and green respectively). (c+d) sphingomyelin (SM) and phosphatidylethanolaime (PE) have no difference in diffusion coefficients.
Why I like this preprint
I always find it fascinating when viruses or bacteria utilise our cells to their own advantage which is exactly what the HIV-1 virus and its Gag protein are doing here. Uncovering the mechanisms behind how viruses can replicate and infect will hopefully lead us to preventing them from doing so. The preprint was very easy to read and understand which can’t always be said for some preprints!
Future directions and questions
What mediates the specificity for Gag to PI(4,5)P2 and cholesterol?
Is this a mechanism many viruses also use?
This work provides an interesting possibility in terms of potential drug target design; if we prevent the interaction between Gag and lipid sequestering can we prevent the formation of the lipid platform HIV-1 needs to assemble and bud from?
References
- Brü, B. et al. The HIV lipidome: A raft with an unusual composition. (2006).
- Honigmann, A. et al. Scanning STED-FCS reveals spatiotemporal heterogeneity of lipid interaction in the plasma membrane of living cells. Nat. Commun. 5, 5412 (2014).
doi: https://doi.org/10.1242/prelights.9324
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