When SARS-CoV-2 first began spreading across the globe, not every lab was equipped to study it directly. The virus behind the current pandemic is highly pathogenic and transmissible, leading the US Centers for Disease Control and Prevention to require many of the same biosafety guidelines that shape the study of diseases such as tuberculosis and Ebola.
As in many moments throughout the last year, the scientific community responded by creatively adapting existing tools to the study of COVID-19. Among these, researchers turned to models of the pathogen such as pseudoviruses and chimeric viruses that can be studied safely in labs with lower biosafety level (BSL) clearance than required for studying the wildtype version, in an effort to expand the study of the novel coronavirus. Pseudoviruses don’t replicate, rendering them harmless, but by replacing their surface envelope proteins with those of SARS-CoV-2, researchers can glean insights into the ways the pathogen infects cells. A chimeric virus is made by inserting the genetic material of one virus into the genome of another, safe surrogate, and these introduced sequences are passed on when the virus replicates.
In addition to their safety, pseudoviruses are “extremely versatile in that you can . . . introduce different envelope proteins and you can introduce mutations, which is making it extremely useful for us to screen a lot of different variants,” says Carol Weiss, a virologist who heads the laboratory of immunoregulation at the US Food and Drug Administration. “If you want to introduce mutations in real viruses, it’s a whole lot more work.”
An approximation of the real thing
Pseudoviruses were first developed in the 1960s, after scientists began studying a vesicular stomatitis virus (VSV) isolated from cattle. In addition to replicating well in culture, they later learned that its surface protein, VSV-G, facilitates entry into all eukaryotic cells, making the virus a useful vector not only as a pseudovirus but as a ferry to deliver DNA into cells for therapeutic purposes. The first Ebola vaccine was developed using a VSV platform, and more recently, the virus has been engineered to seek out and destroy cancer cells.
HIV-based platforms, which came about in the 1980s, have since replaced VSV as the most common model for developing both pseudo- and chimeric viruses. Unlike VSV’s negative-strand RNA genome that must be transcribed once inside the cell, HIV’s positive-strand RNA genome can instantly begin translation, making pseudoviruses based on HIV faster to produce. HIV-based model viruses have now been used in many of the same applications as VSV, with scientists applying them to the study of diseases such as AIDS, SARS, MERS, and influenza.
We wanted to really validate that the tool that we generated did appear exactly, with everything we could throw at it, the same way as SARS-CoV-2.—Sean Whelan, Washington University
To harness these surrogates to study SARS-CoV-2, researchers first needed to prove that their pseudo- and chimeric viruses are viable stand-ins for the real thing. SARS-CoV-2 is a uniquely bulky virus—its genome is roughly 30 kilobases, while HIV and VSV sit around 10 kilobases—and while it is more similar to HIV, none of the three are closely related. Fortunately, both HIV and VSV appear to be compatible for making coronavirus models.
Sean Whelan, a virologist at Washington University in St. Louis, is one of many scientists who has developed a viable chimeric virus platform and quantified its performance in the face of antibodies against the real thing. To do this, he developed two complimentary assays—one for use in infectious disease laboratories with the BSL-3 clearance required to handle live SARS-CoV-2 and another for labs working under a lower, BSL-2 clearance—and studied how each virus responded to a battery of different treatments. It wasn’t enough, he says, to test the viruses’ ability to evade just one type of antibody, so he used monoclonal and polyclonal antibodies and serum from recovered COVID-19 patients—as well as a type of ACE2 decoy protein suggested as a possible therapeutic to draw the virus away from the cells’ own receptor. “We wanted to really validate that the tool that we generated did appear exactly, with everything we could throw at it, the same way as SARS-CoV-2.”
Image Credit: Envato / Amanda Scott
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