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Llamas – those bored-looking, slow-munching camelids from South America – are prized for their wool and leather. Yet beneath their fur and skin, these domesticated pack animals also hide another powerful tool that humans are trying to make use of.
When llamas (Llama glama) are exposed to certain deadly human viruses, scientists have found their bodies create powerful immune proteins unlike any produced in our own species.
Using this knowledge, researchers working at the United States National Institutes of Health (NIH) have now engineered a human-llama hybrid antibody that can subdue one of the craftiest contagions known to humankind: HIV.
The human immunodeficiency virus (HIV) is a wily shapeshifter that can quickly evolve to block human antibodies, which are responsible for latching onto and restraining foreign threats.
"Conventional antibodies are bulky, so it's difficult for them to find and attack the virus' surface," explains biologist Jianliang Xu from the NIH and George State University.
Llama antibodies are different. Like sharks, alpacas, and camels, llamas are one of a few animals known to produce extra-small versions of conventional antibodies, called nanobodies, which are about a tenth the size.
These nanobodies are 'light on their feet' and flexible. Their small size and elongated shape means they can squeeze between the defenses of a virus to smother the most infectious parts of the virus.
To stimulate the production of HIV-specific nanobodies, researchers at the NIH injected a part of the HIV-1 envelope into one, single llama 13 times within one year.
Then, with careful engineering, they took the most potent HIV nanobodies they could find and fused them with parts of a broad-acting human antibody for HIV.
These broadly neutralizing antibodies (bNAbs), which can target multiple strains of HIV, were discovered in some human patients in the 1990s. But even after nearly four decades of research, scientists have yet to create an HIV vaccine or long-acting treatment with bNAbs that can effectively resist the virus' mutations.
On their own, the human antibody and the llama nanobody can neutralize 90 percent of HIV-1 strains, though each targets a different part of the virus. Combined, the double-pronged approach is "ultrapotent", the researchers write. The llama-human chimera can suppress 96 percent of 208 HIV strains in the lab.
That's ten times more powerful than a previously engineered human-llama antibody, made by some of the same researchers.
"These nanobodies are the best and most potently neutralizing antibodies to date, which I think is very promising for the future of HIV therapeutics and antibody research," says biology PhD candidate Payton Chan from Georgia State University.
"I hope one day there will be approval of these nanobodies for the treatment of HIV."
It remains to be seen if the newly engineered llama-human chimera can target HIV infection in living animals or humans, but the fact that the treatment can bind to two of the virus' most vulnerable spots should make it harder for the pathogen to escape the immune system's clutches.
Antibody infusions have recently emerged as a promising way of treating, preventing, or even curing HIV, but previous studies have found a lasting effect requires very specific bnAbs at high doses.
Perhaps llama nanobodies are a way to make these treatments more potent at lower concentrations. How to make the medicine last longer, however, is another challenge.
An antibody treatment for HIV that only needs to be given to patients once a year or so could prove highly effective in a clinical setting. Right now, these treatments require top-ups every few months.
Researchers at NIH are now working on engineering new combinations of llama-human antibodies to see if they can create a treatment with even more powerful effects.
The study was published in Advanced Science.
