Co-evolving Antivirals to rapidly defeat new viruses

Zika. Ebola. Dengue. Influenza. Chikungunya. These are but a few among the growing cadre of viruses that today pose serious health threats to U.S. troops, as well as to civilian populations in the United States and around the world. Vaccines exist for but a few of these infectious diseases. And since these viruses have an uncanny ability to mutate and morph as they reproduce inside their hosts, those few vaccines that do exist are quickly outdated, providing little protection against the latest viral strains. That’s why flu vaccine manufacturers, for example, must produce new versions annually, at enormous expense and with variable year-to-year efficacy.

Ideally, to outpace evolving pathogens, a therapy or a vaccine would adapt in real time, shape-shifting as fast as its targets do. To pursue that radical approach, DARPA today launched its INTERfering and Co-Evolving Prevention and Therapy (INTERCEPT) program.

“We need a new paradigm to stay ahead of these moving targets,” said Jim Gimlett, DARPA program manager. “With INTERCEPT, the goal is to develop viral therapies that are effective against a broad spectrum of viral strains, and that can co-evolve and outpace new strains.”

Viruses are among the simplest infectious entities known. All consist of two main parts: genetic material (DNA or RNA) surrounded by a protein shell. To reproduce, the virus attaches itself to, and then enters, a cell within a host organism and releases its genetic material into that cell. The viral genes then hijack the host cell’s biological machinery, forcing the cell to generate new copies of the viral genome and shell proteins. While still inside the host cell, those freshly minted viral genomes and protein shells assemble into new viruses, which eventually burst from the cell and disperse to infect others.

The goal of the INTERCEPT program is to develop viral therapies that are effective against a broad spectrum of viral strains, and that can co-evolve and outpace new strains.

To disrupt this pernicious process, INTERCEPT aims to harness the potential of Therapeutic Interfering Particles, or TIPs—tiny virus-like entities made of laboratory-grown snippets of genetic material packaged inside protein shells. Like viruses, TIPs can enter host cells, but they have no impact on their host because TIPs lack the genes required to independently hijack a host cell’s genetic machinery. When a TIP-containing cell does get infected by a virus, however, the cell begins producing TIP genome copies that then compete with the virus’s genome copies for the available protein shells. In fact, by design, the benign TIPs get produced in greater numbers than the actual viral genes. As a result, the TIPs are preferentially packaged into new protein shells and emerge in greater numbers from the host cell. In the end, infected host cells produce relatively few infectious viruses and lots of “dud viruses” containing harmless TIP genes, which quickly dilute the real viruses and nip the infectious process in the bud.

“You can think of these TIP-filled envelopes as tiny Trojan horses, but instead of containing warriors they contain pretenders that ultimately outnumber real disease-causing viruses and interfere with their ability to replicate,” Gimlett said. And because TIPs are made of genetic material, he added, they will be subject to mutation and diversification over time just as the genomes of real viruses are. “Once we develop a TIP that works for a given virus, we expect it to generate a steady stream of variants so there will always be a population of TIPs with the right genetic stuff to disrupt any new strains of that virus that may arise.”

In preliminary DARPA-funded studies conducted in cells growing in culture dishes, engineered TIPs reduced viral loads nearly 20 fold. The INTERCEPT program aims to achieve even higher anti-viral efficiencies; test TIP safety and efficacy in animal models; and assess whether, via spontaneous mutations, TIPs can indeed keep up with whatever new tricks actual viruses come up with as they evolve.

The program will focus on three technical goals. The first is to develop TIP candidates that can remain dormant in uninfected cells but can replicate and outcompete a virus after infection, and to assess short-term efficacy and toxicity in cultured cells. The second goal is to conduct long-term (four- to eight-month) studies of safety and efficacy and to assess the capacity of TIPs to co-evolve with a virus. The third goal is to develop computer models that can help inform the design of improved TIPs by predicting the safety, efficacy, and co-evolution dynamics at various scales, from an individual cell to an organism to an entire population.