Biotech Connector presents immunotherapeutic strategies for an HIV functional cure

More than 40 million people worldwide are living with AIDS, and while effective treatment exists, the moment that treatment stops, the AIDS virus rebounds. 

At the most recent Biotech Connector seminar series, three local HIV/AIDS researchers presented their research into developing a lasting treatment for HIV. 

Each took a different approach to tackling the HIV cure challenge, focusing on different parts of the immune system: CD8+ T cells, CD4 cells and B cells. 

Investigating the CD8+ T cell response

Adrienne Swanstrom, Ph.D., a scientist in the AIDS and Cancer Virus Program at the Frederick National Laboratory for Cancer Research presented research on CD8+ T cells. She noted that the CD8+ T cell response typically is deficient in fighting HIV infection.

Swanstrom said the key question has been: “Are there deficiencies in CD8+ T cell quantity, quality, timing, and/or location that prevent an effective antiviral CD8+ T cell response from developing and acting at foci of viral infection and replication?” 

To answer this question, her team used a nonhuman primate model of HIV infection with a barcoded simian immunodeficiency virus (SIV), which was developed by the AIDS and Cancer Virus Program. 

The barcoded virus contains a unique short sequence of nucleotides (i.e., a barcode) that allow the scientists to track individual virus lineages. With these tools, they tested whether infusing engineered SIV-specific CD8+ T cells in the animals prior to infection would reduce the viral impact. 

They conducted the engineered CD8+ T cell adoptive transfer experiment in six pairs of animals, with each pair including a control animal and an active treatment animal. In all six pairs, the control animal had a higher viral burden, higher viral growth rate and more detected barcodes at the acute viral peak than those that received active cells. 

These results demonstrate that the engineered SIV-specific CD8+ T cells reduced viral growth and replication.

Swanstrom said the results of this experiment provide “direction for vaccine development and potential cellular immunotherapy approaches.”

She also presented new and upcoming research to optimize engineering methods and antigen receptor design, leveraging learnings from the cancer immunotherapy field and applying them to HIV. 

Helping the helper cells

Jeff Galvin, CEO and founder of American Gene Technologies, presented research from a phase I clinical trial involving seven patients. His research focused on CD4 cells, a type of white blood cells also called helper T cells. 

“HIV is really good at eliminating its own category of T cells immediately when it enters the body during the acute phase,” Galvin said. “It will go ahead and defeat the part of the immune system that should be able to fight it.”

In the study, CD4 cells were removed from the participants’ blood, genetically modified, and returned to the patient. 

“We want to take that person’s CD4 cells and essentially give them body armor,” Galvin said.

This approach was inspired by elite controllers, people whose immune system is able to suppress the virus, maintaining undetectable viral loads without antiretroviral therapy (ART). Less than one percent of people with HIV are elite controllers. 

Following the CD4 cell treatment, the investigators observed an increase in HIV-specific CD4 cells that persisted for over two years. After 18 months, six of the patients went off ART, and all six showed an immune response as the virus rebounded. 

When they went off ART a second time, they had lower viral rebound and faster re-suppression of the virus once back on ART.

The researchers will soon be starting a phase II study with 36 participants. 

Isolating broadly neutralizing antibodies

Michelle Zemil McCrea, a program manager at the Henry M. Jackson Foundation, presented on broadly neutralizing antibodies (bNAbs) as a promising countermeasure to HIV.

However, McCrea explained that contemporary strains of HIV are becoming increasingly resistant to available bNAbs, making the “isolation of next-generation bNAbs very important for the development of effective antibody-based prevention and therapeutic products.”

To create these bNAbs, investigators take B cells (antibody-producing white blood cells) with HIV-specific B cell receptors from people who are living with HIV or have been vaccinated. They isolate the B cells and generate heavy and light chain expression plasmids, which they use to produce and purify monoclonal antibodies (mAbs). 

She described three different approaches to isolating and producing mAbs, which are laboratory-created proteins that mimic natural antibodies.  After characterizing the mAbs, they develop the top hits. 

Via this method, her team has developed a promising candidate: MHRP.AF25, a next-generation and ultrapotent bNAb.

“Looking forward, we intend to test whether MHRP.AF25 can mediate Fc effector functions and kill infected cells, which would be very important for a cure strategy,” McCrea said.

Join the next Biotech Connector

Join us on November 12 at 8 a.m. for the next Biotech Connector. This quarterly event is hosted by the Frederick National Laboratory for Cancer Research in collaboration with the Frederick County Chamber of Commerce.