A team of scientists including Texas A&M College of Veterinary Medicine & Biomedical Sciences (CVM) associate professor of immunology Dr. Michael Criscitiello have achieved a significant step forward in HIV research, eliciting broadly neutralizing antibodies (bNAbs) to the virus by immunizing calves.
The National Institutes of Health (NIH)-supported scientists reported the findings in a paper published online July 20 in the academic journal Nature. Those findings offer insights for HIV vaccine design and support further study of modified bovine antibodies as HIV therapeutics or prevention tools in humans.
Researchers have observed that about 10-20 percent of people living with HIV naturally develop neutralizing antibodies to the virus, but usually only after nearly two years of infection. These neutralizing antibodies have been shown in the laboratory to stop most HIV strains from infecting human cells and to protect animal models from infection.
However, scientists have so far been unsuccessful in prompting the human immune system to produce these antibodies through immunization. Further, while bNAbs isolated from people with HIV infection have demonstrated promise in primate studies and have entered human studies for HIV prevention and treatment, questions remain about whether effective antibodies could be produced rapidly and at a scale suitable for widespread distribution.
The researchers have determined that cattle may offer some help in solving these problems.
“This work is exciting because a structural and genetic oddity in cattle antibodies appears to allow them to easily and quickly make effective antibodies to HIV that humans cannot,” Criscitiello said. “The cattle antibodies may themselves be useful—with a few tweaks—in humans.”
While bovine neutralizing antibodies are not likely suitable for clinical use in humans in their current form, exploring this rapid production may help answer important research questions.
“From the early days of the epidemic, we have recognized that HIV is very good at evading immunity, so exceptional immune systems that naturally produce broadly neutralizing antibodies to HIV are of great interest—whether they belong to humans or cattle,” said Dr. Anthony S. Fauci, NIAID director.
“We never dealt with the entire HIV virus here (at Texas A&M), but the cattle received immunizations containing a protein designed to mimic a surface protein on HIV,” said Criscitiello, who coordinated the A&M efforts with Scripps, managed the animal work, and analyzed the antibody immunogenetics.
While no one knows definitively why these powerful antibodies evolved in cattle, one theory holds that the animals’ long HCDR3 loops are tied to their extensive gastrointestinal systems. Cattle and other ruminant animals have multi-chambered stomachs and a robust population of bacteria in their digestive tracts to help break down a diet of tough grasses. However, these bacteria can pose an infection risk if they escape the gut, so cattle with a versatile mechanism for producing potent antibodies would greatly benefit from the increased protection.
“A minority of people living with HIV produce neutralizing antibodies, but only after a significant period of infection, at which point virus in their body has already evolved to resist these defenses,” said Dennis R. Burton, Ph.D., a lead author on the study, director of the NIH’s Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery and scientific director of the IAVI Neutralizing Antibody Consortium at the Scripps Research Institute. “Unlike human antibodies, cattle antibodies are more likely to bear unique features and gain an edge over complicated HIV immunogens.”
Further study on how this mechanism contributed to the elicitation of bNAbs to HIV in cattle may inspire novel approaches to HIV vaccine development.
“HIV is a human virus,” said Devin Sok, a study leader and IAVI collaborator at the Scripps Research Institute, “but researchers can certainly learn from immune responses across the animal kingdom.”
Researchers may also explore mimicking or modifying the potent isolated bNAb, or those like it, to develop antibody-based HIV therapeutics and prevention tools, as well as treatments for other pathogens that have evolved to avoid human antibody responses. Because the current research indicates that the bovine immune system may typically work quickly to produce effective antibodies against difficult pathogens such as HIV, immunizing cattle and discovering such antibodies may become a useful approach to ensure these tools are readily accessible.
To read the full report in Nature, visit http://www.nature.com/nature/journal/vaap/ncurrent/full/nature23301.html, and to see the full press release, visit the National Institute of Allergy and Infectious Diseases website at https://www.niaid.nih.gov/news-events/nih-supported-scientists-elicit-broadly-neutralizing-antibodies-hiv-calves