Ann Hessell, Ph.D., modifies lab-made antibodies to aid HIV fight.
Although antibodies are commonly discussed by the general public right now due to the COVID-19 pandemic, many scientists have focused on the magic immunological molecule for decades.
One of them is Ann Jones Hessell, Ph.D., a research associate professor at OHSU’s Oregon National Primate Research Center, or ONPRC. Hessell seeks to understand and re-engineer antibodies as part of her search for better HIV treatment and prevention.
Today, people living with HIV take a regimen of daily oral anti-retroviral therapy, or ART. Although a combination of various ART pills is usually effective at keeping HIV levels so low that the virus is undetectable, it isn’t perfect. Some HIV variants have developed immunity against these medications, and ART can also be toxic or cause adverse effects for some patients.
Scientists like Hessell are exploring a potential alternative treatment: lab-made antibodies, also known as monoclonal antibodies and commonly called broadly neutralizing antibodies by HIV researchers. The human body naturally produces antibodies to recognize and remove toxins and pathogens, but HIV is a quickly changing virus that easily evades our natural immune system. Lab-made antibodies that are designed to precisely target HIV could give our body a leg up, much like they are already being used to treat COVID-19 and some cancers.
In 2007, Hessell was lead author on a now-widely cited Nature study that determined antibodies must use multiple ways to fully protect against HIV infection. The pre-clinical study was the first to evaluate engineered antibodies in nonhuman primates. It used altered antibodies that can’t interact with critical immune cells to explore if infection by the monkey form of HIV can still be prevented .
The study specifically pinpointed that pathogen-killing immune cell Fc receptors as being critical in signaling immune killer cells to prevent infection and to kill any already infected cells. Hessell and her colleagues reported that animals given modified antibodies without working Fc receptor binding regions had dramatically larger viral levels than those given the same antibody with an intact Fc. This was the first report of antibody-Fc receptor interaction as being key to efficiently blocking HIV infection. The finding indicated lab-made antibodies with well-functioning Fc receptors held promise in treating HIV, and prompted years of follow-up research by Hessell and many others.
Fifteen years later, Hessell has published her latest HIV study involving engineered antibodies and the critical role of antibody-Fc receptor interactions. The Feb. 3 Nature Communications study examined how changes to the Fc region in a specific lab-made antibody known as 10E8v4 affected its ability to fight the monkey form of HIV. This time, in addition to only knocking out Fc receptor binding, Hessell and colleagues aimed to improve it by: 1) making 10E8v4 able to trigger enhanced complement activity and 2) increase Fc receptor binding strength. After confirming these improvements in the laboratory, they evaluated their impact in monkeys. Three versions of the 10E8v4 antibody were tested in animals: unmodified, enhanced and disabled. While lab studies led to improvements with the enhanced antibody in the lab, those improvements didn’t carry over into animals. Instead, only the antibody’s unmodified version with naturally occurring Fc interaction strength was found to reduce virus levels in the blood and tissues.
Although this latest study isn’t expected to immediately result in a new HIV treatment, Hessell considers it a success. The study marked the first meaningful test of enhancing a complement immune response to HIV in a nonhuman primate model . And, given that scientists are increasingly finding a lab-made antibody’s ability to reduce HIV is contextually dependent, their team’s and other, yet-to-be-discovered antibody modifications could be applied to a different antibody that ultimately becomes an effective HIV treatment.
In the meanwhile, she and her colleagues will continue to adjust and revise their ongoing lab research, testing new ways to improve HIV antibodies. While decades of HIV research, including recent clinical antibody trials, accelerated the development of antibody-based treatments for COVID-19, the search for a similar HIV therapy continues.
This research was supported by the National Institutes of Health (grants R01 AI129801, P51 OD011092 and U42 OD023038).
All research involving animal subjects at OHSU must be reviewed and approved by the university’s Institutional Animal Care and Use Committee (IACUC). The IACUC’s priority is to ensure the health and safety of animal research subjects. The IACUC also reviews procedures to ensure the health and safety of the people who work with the animals. The IACUC conducts a rigorous review of all animal research proposals to ensure they demonstrate scientific value; justify the use of live animals.
— Written by Franny White, senior media relations specialist