Siddarth Venkatesh

Presented by Paul Bieniasz
B. Tech, University of Madras
Ph.D. Auburn University
Mechanism and Evolutionary Origins of HIV-1 Virion Entrapment by Tetherin

For his thesis project Siddarth Venkatesh worked on a protein, called tetherin, that is expressed in response to viral infection. Tetherin is a coiled-coil cell surface protein that traps nascent enveloped virus particles as they bud through the membranes of infected cells, preventing them from going on to infect other cells.

Sid worked on two problems: First, how precisely does tetherin work? By designing biologically active but cleavable and tagged derivatives of tetherin, Sid showed in molecular detail exactly how tetherin ensnares virions.

The second question that Sid asked was: From where did tetherin arise? It has a nearly unique configuration and no clear homology to any other protein. Working with another student, Daniel Blanco-Melo, Sid built a strong case that tetherin arose via duplication of a neighboring, similarly configured but more ancient gene, PV1, that encodes a component of caveolae. Most compellingly, Sid showed that a small change to PV1 could transform it, functionally, into tetherin.

Sid was determined, dedicated and talented but also generous, kind and always cheerful. His skills and deep commitment to his science were most obvious in the extraordinary quality of his work. His passion for science manifested itself in another way too; he is the only student I have known who was so moved by what he was doing in the lab that he composed poetry about it:

My name is tetherin, and my fortunes are on an upward spiral,
For I am an effector of intrinsic immunity; indeed, I am antiviral.
So when a virus is sensed, and the time is ripe,
I am induced by interferon in almost any cell type.
My amino acid sequence can be wild-type or chimeric,
But in order to be potent, I have to be dimeric.
With an anchor in the cell, and another in the virion,
Axially configured, I trap them by the million.
I have a predilection that is not entirely insane,
I’d rather insert my GPI anchor into the viral membrane
This facilitates endocytosis of the rogues that I hold,
Or, alternatively, I function as a signaling scaffold.
All in all, our struggles always live up to their billing,
My life in genetic conflict — endlessly fulfilling!

Today Sid is receiving his second Ph.D. (his first was from Auburn University in chemical engineering). He has just (finally) moved on to postdoctoral work on the microbiome with Jeff Gordon at Washington University in St. Louis. We wish him the very best in his
new endeavors.