How to Catch a Virus…on Purpose

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Science & Technology Health Research

How to Catch a Virus…on Purpose

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Medical advancements over the last several decades have made great strides in the treatment of HIV. Pharmaceutical treatments are able to contain and reduce a patient's viral load to the point where it is nearly undetectable. But a cure remains frustratingly elusive due to the virus's ability to evade the immune system. Researchers from Drexel University and the University of Pennsylvania, who specialize in modulating immune responses, have offered a new approach - one that's likely familiar to anyone who has dealt with pest removal: setting a trap.

Recently reported in the journal Biomaterials, the team demonstrated how to disguise a liposome - a type of hollow fat bubble found throughout the body - as an immune cell, creating what they call a "nanotrap" for HIV. They report that the biological ruse is capable not only of luring and ensnaring the virus, but also tagging it as an intruder, which triggers an immune response.

A Greedy Virus

The canny tactic represents a new approach in therapeutic vaccine development, which has primarily focused on directly attacking the virus, rather than enabling natural immunity.

"The concept of 'nanotrap' therapeutic vaccines takes advantage of the fact that HIV is a greedy virus," said Peter Deak, PhD, an assistant professor in Drexel's College of Engineering and Computing, who led the research. "Yes, it's great at evading the immune system through mutation and hiding in genetic material, but it has an insatiable drive to infect T cells. By creating a bait molecule that looks like a T cell, we render it vulnerable to the body's natural immune response by shining a molecular 'spotlight' on it, so all immune cells recognize it."

Deak's research group arrived at the approach after years of developing minimalist interventions that influence the immune response to allergens and transplanted organs.

Armed with their deep knowledge of the system's natural behavior, wrought from this research, the group teamed with colleagues from Drexel's College of Medicine and Penn's Department of Chemistry to better understand HIV's evasive maneuvers.

"We now know that the virus mutates so frequently that, no two infections are the same," said Elias El Haddad, PhD, a professor in Drexel's College of Medicine who was a co-author of the research. "In fact, within just a couple of days of infection, we see that the original virus mutated so readily that hundreds of new virus isolates are generated."

In addition, El Haddad noted, the virus can integrate itself within genomic DNA and hide forever. This happens so quickly that by the time the infection is diagnosed, the virus has already found its hiding place.

"This makes it difficult to bring the virus out from hiding. All together, these challenges present huge difficulties to come up with curative treatment that targets the virus," he said.

Fortunately, tailoring a response to combat a biological intruder is precisely the function of the immune system - when it's able to make a proper identification, according to Deak.

"Rather than developing an outside intervention that targets physical features of the virus, such as its protein spikes, our concept is simply to draw attention to its presence long enough for the body to formulate its own plan of attack," Deak said. "We're looking at a universal approach using natural pathways that could be effective regardless of the viral strain or mutation."

From Allergies to HIV Therapy

Deak's approach draws on techniques he used during his doctoral research studying the immune response's role in allergic reactions. During his studies, Deak produced a variety of coated lipid particles designed to draw out immunoglobulin E - antibodies produced in trace amounts that play an important role in causing an allergic reaction - in an effort to develop a preventative treatment for peanut allergies.

"This work gave me a unique perspective on how the immune system functions - both when it's effective and when it's overactive," Deak said. "I was particularly drawn to this research because I've had allergic reactions to peanuts and wanted to help others dealing with similar allergies. But it made me realize just how narrow the difference is between a healthy immune response and a dangerous allergic reaction. I saw that giving the immune system the slightest stimulus can tip the delicate balance."

Around the same time Deak was learning how to coat lipids to entice antibodies, HIV researchers were beginning to understand how the virus uses a similar strategy to disguise itself - coating its tell-tale protein spikes with sugar molecules - and develop approaches to penetrate this protective coating. Presented at a conference, research on the virus's familiar deception, and treatment strategies that sought to circumvent the coating, seeded the inspiration for Deak's strategy.

"I thought, 'why bother trying to evade the coating when we could just add another one on top of it?' - one that clearly identifies it as a virus," Deak said. "It's a strategy similar to the explosive dye pack banks use to help authorities catch robbers 'red handed.'"

Building a Nanotrap

To create their version of the dye pack, the nanotrap, Deak's team loaded up a liposome with three types of molecules. Ligands that mimic CD4 immune cells - the bait; fusion inhibitors that bind to and envelop HIV proteins - the trap; and R848, a synthetic molecule known to trigger a potent immune response - the dye.

"The first critical step in the nanotrap design was finding a molecule to serve as a universal bait for the continually evolving HIV virus," said Irwin Chaiken, PhD, an emeritus professor in the College of Medicine and co-author of a study into structural treatment approaches for HIV. "We needed something that worked with most HIV strains."

The team tried several options before settling on CJF-III-288, a molecule developed by Amos B. Smith III, PhD, a University of Pennsylvania researcher, in collaboration with Cameron Abrams, PhD, the Bartlett-Barry endowed professor in Drexel's College of Engineering and Computing, that binds to a functionally essential site on the HIV surface spike protein.

To test the nanotrap, the team used a pseudovirus, a synthetic viral particle designed with the physical characteristics of HIV. After giving the pseudovirus a 24-hour head start in a mouse model, the team introduced its nanotrap therapeutic vaccine and tracked the immune response.

They found that after just one injection, the vaccine had generated the sort of broad immune response associated with the body's front-line defense against an infection.

"We found a robust production of both T-cells and B-cells; this means that not only was the nanotrap successful in capturing the HIV virions - triggering T-cell production - but also in a broad immunity, meaning targeted against many parts of HIV, which is more likely to be effective," Deak said. "While this is just the first step toward demonstrating the potential of nanotrap therapeutic vaccines, seeing this type of immune response is certainly a promising indication."

The team also microscopically observed the uptake of pseudoviral particles by the liposome. This indicates that not only does the bait molecule draw them away from healthy cells, but it is also able to detain them while the immune system prepares to respond.

Path of Potential

Due to durability of its design, HIV could just be the first target of the nanotrap vaccine. Preliminary findings suggest that it could remain effective, regardless of how HIV mutates, because it targets a behavioral pattern, rather than a physical vulnerability. But Deak suggests that it could just as easily be tailored to trap other viruses with surface proteins, including hepatitis, long covid and herpes.

"Nanotrap therapeutic vaccines are intentionally designed to be modular," Deak said. "All three of the components - ligand, agonist and liposome platform - can readily be altered. Although we are presenting this as a first-in-class HIV therapeutic vaccine, we believe it has great potential with continued testing and optimization."

For now, the team plans to continue its pursuit of HIV with further testing on infected cells to study how effective the immune response triggered by the nanotrap vaccine could be at preventing infection.

This research was supported by the National Institutes of Health.

In addition to Deak, Chaiken and El Haddad, Ted Kang, Charles Ang, PhD, Gabriela Canziani, PhD, Heba Elkateb, PhD, and Divine Thomas, DO, from Drexel; and Derek Yang, PhD, from the University of Pennsylvania, contributed to this research.

Read the full paper here: https://www.sciencedirect.com/science/article/pii/S0142961226001481

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