Conventional hepatitis C virus (HCV) treatments target only one component of the replication complex at a time. Eventually, HCV evolves within an individual and drug resistance develops leading to the need for expensive combination therapies.
The Lindenbach Lab led by Brett Lindenbach, PhD, Associate Professor of Microbial Pathogenesis at Yale School of Medicine, and a member of the Yale Cancer Center Molecular Virology Research Program, is conducting promising research that may lead to medications that target multiple components of the replication complex and are exponentially more effective.
Dr. Lindenbach is studying the life cycle of HCV, specifically how the viral replication proteins fit together to make a functional replication complex – much like an aspiring auto mechanic may disassemble an engine to figure out how it works as a whole. What he’s determined is that two of the viral proteins, NS5A and NS5B, are synergistic (thus signaling a vulnerability to combination drugs), and are essential for the HCV “machine” to work. Auspiciously, both already have targeted therapies – a great starting point for future medicines.
Studying how HCV particles are constructed is providing additional fodder for potential therapeutics. In particular, Dr. Lindenbach is searching to uncover the structure of HCV particles and understand how they are assembled. These basic questions have led to the discovery that virus particles interact with serum lipoproteins, although the ‘hows’ and the ‘whys’ are still under inquiry. In particular, Apolipoprotein E (Apo-E) is being examined for its importance in interactions between virus particles and serum lipoproteins.
Furthermore, Dr. Lindenbach has uncovered that some nonstructural proteins (viral proteins expressed within infected cells but not within viral particles) are involved in making virus particles. In particular, NS2 and NS3 proteins participate in coordinating viral replication and assembly. This synergy is important in the formation of the nucleocapsid, the basic structure of a virus minimally consisting of a protein coat (capsid) surrounding the viral genome– again, a relationship that reveals a potentially advantageous weakness.
Each discovery brings Dr. Lindenbach and his researchers closer to translating their knowledge into highly effective treatments for HCV that will ultimately lead to fewer HCV-related cancers.
Submitted by Emily Montemerlo on August 07, 2017