Virus World

A host of disease-causing viruses called arenaviruses lurk in animal populations in various parts of the world, sometimes crossing over into humans. When they do cross over, they can be lethal, and only very few treatments exist. Researchers led by scientists at the Weizmann Institute of Science have now devised a clever decoy for these viruses that may keep them from spreading in the body. Two disease-causing arenaviruses, known as Junín and Machupo, circulate through rodent populations, mainly in South America, and they can infect humans when people come in contact with affected rodents. Similar to Ebola, these diseases can cause the body to "bleed out," and the only treatments, to date, are risky and complex, as they are taken from the blood of survivors.

The present study, which was reported in Nature Communications, arose from an earlier research question in the group of Dr. Ron Diskin of the Institute's Structural Biology Department: how are certain arenaviruses able to move from rodents or other animals into humans? Comparing these viruses with members of the arenavirus family that are not infectious to humans, the researchers noted that the non-infectious viruses did not completely fit a particular receptor - a protein complex on the cell membrane - that serves as a viral entry point into human cells. But curiously, those that do infect humans were also not a perfect fit. They were just good enough to get by. This observation led to another insight: Maybe the rodent cell receptors, which were a much better fit to the "entry" proteins on the viruses, could be used to intercept the viruses and lure them away from the human cells. There had been earlier attempts to develop such decoys - "sticky" molecules designed to attract virus proteins - explains Diskin, but these were based on the structures of human receptors, so they were identical to the ones on the body's cells and thus unable to compete effectively. In contrast, a molecule based on a rodent receptor, he and his team reasoned, could far outcompete the human ones for binding to the virus.

Dr. Hadas Cohen-Dvashi, in Diskin's group, led the next stage of the research, in which she "surgically removed" the very tip of the rodent receptor to which the virus binds and engineered it onto part of an antibody. The newly resulting molecule was called "Arenacept." Then the group began testing this molecule - at first against "pseudoviruses," engineered virus-like complexes which carry the entry proteins but that are not dangerous. Already at this stage, and in collaboration with the group of Dr. Vered Paler-Karavani of Tel Aviv University, the researchers noted that Arenacept not only bound strongly to the viruses, it recruited parts of the immune system to mount an attack against the viral invasion....

Published in Nature Commun. (January 3, 2020):

https://doi.org/10.1038/s41467-019-13924-6

A new study, published in the August 8, 2019, issue of Cell by a team of researchers led by Instructor Kathryn Hastie, Ph.D., and Professor Erica Ollmann Saphire, Ph.D., at La Jolla Institute for Immunology (LJI),  identified and then reverse engineered the molecular properties shared by antibodies that are particularly efficient at inactivating or “neutralizing” the virus. The team’s findings also revealed that most neutralizing antibodies bind to the same spot on the surface of Lassa virus, providing a map for rational vaccine design.As this year's Lassa fever outbreak in Nigeria is finally ebbing, the total tally came to more than 600 infected people, one-quarter of them dead. Thousands more die each year, uncounted in rural villages throughout West Africa. With an annual wave of infections and new viral strains emerging, it has never been more important to understand the characteristics of a broadly protective immune response in order to develop effective treatments, or better yet, a vaccine.

“The beauty of structural biology is that it gives you the ability to dissect the molecular details at high resolution to explain precisely how something works,” says structural immunologist Ollmann Saphire. “Once you do, you have a blueprint to engineer potent immunotherapeutics or a vaccine that elicits the desired immune response.”

Identified 50 years ago and named for the town in Nigeria where the first known cases cropped up, Lassa virus is endemic in West Africa where it infects hundreds of thousands of people every year. For the majority of infected people, symptoms are mild and the infection mostly goes undiagnosed. But in 20 percent of patients, the disease causes a more serious illness including neurological symptoms and hemorrhage, which can result in multi-organ failure and death.

For the current study, Hastie compared the structure of three different neutralizing antibodies of varying potency—high, moderate and low—bound to the glycoprotein. The side-by-side comparison highlighted specific amino acid residues that drive high potency and enabled the researchers to precision-engineer mediocre antibodies to turn them into highly effective ones.

“Not only were we able to increase the antibody’s potency, which means you can deliver much less antibody, we were also able to make it pan-Lassa. It can hit every Lassa virus lineage characterized so far,” says Hastie.  But few naturally infected people generate neutralizing antibodies and current vaccine efforts focus on eliciting T cell immunity. “Historically, researchers have found that development of antibodies is not a good correlate of protection in natural Lassa infections,” says Hastie. “It is actually very difficult to induce neutralizing antibodies.” 

The study was published in Cell on August 8, 2019:

https://doi.org/10.1016/j.cell.2019.07.020