Mutant HIV viruses fight new infections in two labs

A pair of brothers working in laboratories on opposite coasts of the U.S. are brewing a new approach to fighting viruses, one that’s drawn interest from the military for protection against the threat of infections such as Zika and Ebola.

The experimental treatment pursued by Ariel Weinberger, a Harvard University biologist, and Leor Weinberger, a virologist at the University of California at San Francisco-affiliated Gladstone Institutes, deploys a tweaked, safe version of a virus to overwhelm the form that invades and kills cells. While it’s very early — the approach has only been tested in test tubes and animals — the U.S. government is ready to invest in developing the idea and seeing whether similar mutants can protect against other diseases.

Each new outbreak that shakes the globe, whether it’s Zika spreading across the Americas or a new worldwide strain of deadly flu, is a reminder of the difficulty of fighting emerging viruses, many of which evolve quickly to frustrate and evade drugs. In a connected world where diseases spread via air travel, new ways to fight them are vital, said Ariel Weinberger, a member of Harvard’s Wyss Institute for Biologically Inspired Engineering.

“Diseases transmit — current therapeutics don’t,” he said. “Diseases evolve — current therapeutics don’t. And diseases persist for lifetime and current therapeutics obviously need to be constantly re-administered.”

The brothers are studying bits of genetic material called therapeutic interfering particles, or TIPs, that while known for decades have just recently shown potential to snuff disease outbreaks.While their potential for side effects still must be understood, and effectiveness in humans remains unstudied, the Weinbergers have received funding from the U.S. Defense Advanced Research Projects Agency for exploratory studies of TIPs, and in April DARPA issued a call for more proposals. The agency is interested in looking at a variety of TIPs, each primed to fight a different disease.

Viruses grow by squirting their genes into a cell, which hijacks its protein-making machinery to produce the ingredients of viral copies. Diverted from its own normal functions, and sometimes burst apart by the viruses’ mass exit, the host cell usually dies.

In the 1940s, however, a Danish scientist named Preben von Magnus discovered that flu viruses sometimes create non-infectious mutant offspring. These incomplete progeny function like parasites, thwarting the ability of normal viruses to grow and spread and competing with them for needed proteins.

These faulty viruses are the basis for the TIPs concept, which Leor Weinberger is using to battle HIV in laboratory dishes. The engineered virus hibernates in cells until the arrival of HIV, when the lethal virus stimulates TIPs to replicate alongside it. Because TIPs genes are shorter than HIV’s, they duplicate faster — 10 times faster, in the Weinbergers’ experiments. That allows TIPs to preemptively grab resources — in particular, the protein shells that allow HIV to leave the infected cell and find new hosts. As TIPs mutate, they may also continue to evolve along with the lethal viruses as they compete with them.

The brothers’ mathematical modeling suggests that if TIPs can outrace the growth of the normal virus, these benign particles will keep the disease under control. DARPA is looking at TIPs for a potentially speedy response to outbreaks like Ebola, which killed more than 11,300 people in West Africa between 2014 and 2016. The Weinbergers are applying for support, as is closely-held VirionHealth Ltd., which is investigating TIPs in the U.K.

“We’re looking at a situation where it’s getting easier and easier for nefarious people or communities or countries to engineer their own viruses,” Jim Gimlett, a program director at DARPA, said by phone. “So the more tools we have to respond rapidly to new viral strains we’ve never seen before is definitely a national security concern.”

The road to that goal is long, with many questions along the way. To fight some viruses, TIPs would likely have to integrate into human DNA, a process that has been linked to cancer in other forms of gene therapy. One concern is whether installing TIPs in a cell’s DNA will lead to side effects, said Robert Gallo, head of the Institute of Human Virology at the University of Maryland School of Medicine and a co-discoverer of HIV.

“The manipulations are doable, the questions are if it’ll be practical,” he said in a telephone interview. “It’s too early to throw cold or hot water.”

TIPs’s DNA integration has been shown to be safe in many experiments, and there are many viral diseases that TIPs could fight without entering cellular DNA, Ariel Weinberger said. Animal and human testing are still needed to fully answer these questions, said Gallo, who is on Gladstone Institutes’ scientific advisory board but hasn’t worked with the Weinbergers.

The TIPs strategy has shown some positive results in animal tests against flu, a virus that constantly evolves and kills thousands of people annually around the globe. Mice that were given a form of TIPs resisted extreme doses of flu virus, according to Andrew Easton, a professor at the University of Warwick and one of the co-founders of VirionHealth. When tested in ferrets, a closer model for human flu, TIPs reduced symptoms more than Roche AG’s Tamiflu antiviral, according to an article published in the Journal of Virology in 2014. VirionHealth is seeking investors, and plans to begin testing TIPs in humans in the next four to five years, Easton said.