Regulation of HIV-1-induced cell-cell fusion by host factors
I was born and raised in Cyprus, and completed my Genetics BSc at the University of York in England. As part of my BSc, I spent a year working as a research scientist at AstraZeneca. I joined the CMB PhD program in 2009, and became a member of the Thali lab in August 2010. In the summer of 2011, I attended three conferences and presented a poster of my work at two of those (Retroviruses at Cold Spring Harbor Laboratory, and the Gordon Research Conference on Fusion). I am currently preparing a manuscript for submission in February 2012.
My work currently focuses on the mechanism underlying host regulation of HIV-1-induced cell-cell fusion. Tetraspanins are small transmembrane proteins considered to be membrane scaffolds, which form membrane microdomains and recruit other partner proteins, including integrins and EWI-2. Tetraspanins have been found (by our group and others) to repress the fusion of HIV-1 virions to target cells, reducing viral infectivity, while also repressing viral Env-dependent fusion between infected cells and uninfected target cells. Tetraspanins are enriched at viral assembly and budding sites, and incorporated into virions. Interestingly, while
HIV-1 infection results in the overall downregulation of tetraspanins from the cell surface, viral Gag also specifically traps the tetraspanin
CD9 at assembly sites, suggesting that the role of tetraspanins in HIV-1 infection is not merely that of a host restriction factor. In fact, the primary mode of spread of HIV-1 within the infected host is through cell-to-cell transmission, during which the fusion of infected and uninfected cell would be detrimental to viral spread, suggesting that the virus may be utilizing tetraspanins to its benefit by preventing cell-cell fusion during transmission.
Our most recent work indicates that different tetraspanins may play different roles in this process. The tetraspanin CD63 retains its ability to repress fusion despite mutations, truncations, or domain replacements in the protein. Conversely, in the case of CD9, multiple domains are required for its ability to repress fusion. Intriguingly, the large extracellular domain of CD9 appears to be required for the repression of cell-cell, but not virus-cell fusion. In parallel, we have utilized a small panel of fusion inhibitors with known specificity, in order to determine the stage of the fusion process at which CD9 acts.
This strategy has led us to conclude that CD9 represses fusion at a very late stage, likely during the transition between hemifusion (merging of the outer lipid leaflets) and fusion pore formation. This would suggest a biophysical effect of tetraspanins on the membrane at the site of fusion. Interestingly, we also have preliminary evidence that tetraspanins may increase the rigidity or stiffness of the virion envelope, which would reduce its ability to fuse with the target membrane. We now have new tools developed by colleagues in order to study fusion in live cells at high temporal resolution. Elucidating the molecular details of the way tetraspanins regulate HIV-1 fusion is likely to provide valuable insight into the host-virus interplay that ultimately results in the dissemination of virus within the host.
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