Six Researchers, One Goal

From reducing the HIV reservoir to modifying immune cells, newly funded studies by amfAR researchers underscore the idea that any cure intervention will likely incorporate not only an innovative approach but also a combination of methods.

Waking Up HIV

In a person living with HIV, antiretroviral therapy (ART) is able to suppress the virus to undetectable levels and stabilize the immune system. But these regimens are unable to reach the reservoir, composed of latently infected cells that rebound once ART is stopped. Targeting the HIV reservoir, then, is key to any cure strategy.

Reactivating replication-competent cells in the reservoir seems counterintuitive but the approach makes sense—reservoir cells are hard to detect so activated cells make for easier targets. One wakeup method involves latency-reversing agents (LRAs)—chemicals capable of activating HIV at the level of gene transcription. Once activated, the HIV-infected cells would potentially be vulnerable to attack by immune cells or ART.

But while very potent in the test tube, LRAs have been a disappointment clinically. Alexander Pasternak, PhD, of the Academic Medical Center of the University of Amsterdam in The Netherlands will use his grant of $383,742 to test his theory that current LRAs are acting on insufficient targets and are thus incapable of stimulating HIV at points other than transcription. Working with T cells from people with HIV taking ART, he will attempt to identify novel combinations of LRAs that can remove all obstacles to full reservoir activation.

Reducing the Reservoir

With a $480,000 grant Adam Spivak, MD, of the University of Utah, Salt Lake City, is testing the ability of the cancer drug dasatinib to reduce the HIV reservoir. Used in the treatment of certain types of leukemia, dasitinib blocks T cell proliferation, a fundamental mechanism of HIV persistence and control of HIV reservoir size. Previous case studies have shown it to be more effective than other treatments at reducing the size of the reservoir in people living with HIV. Dr. Spivak’s team will use blood samples from three ongoing clinical trials funded by the National Institutes of Health to test not only the effect of dasatinib on reservoir size, but also other measures of immune function and viral diversity.

Supercharging Immune Cells

Two amfAR researchers are testing immune-based therapies to control the reservoir—genetically engineered B cells (white blood cells that are a key part of the immune system) and a cancer drug that could potentially enlist the immune system to fight HIV.

Yiming Yin, PhD, of Boston Children’s Hospital, is using a grant of $240,000 to genetically engineer B cells, imbuing them with the ability to target three critical portions of the HIV envelope. Dr. Yin is testing a hypothesis that B cells expressing antibodies capable of broadly neutralizing HIV variants could replace ART and reduce the size of a person’s HIV reservoir.

Monkeys will be given these genetically engineered cells and then immunized with an mRNA vaccine expressing the HIV envelope; the function of those B cells will be assessed. Dr. Yin hopes to determine whether the B cells can suppress rebound of the HIV relative, simian-human immunodeficiency virus (SHIV), in SHIV-infected monkeys following treatment interruption.

With a grant of $480,000, Michael Peluso, MD, of the University of California, San Francisco, will test the ability of the drug N-803 to suppress HIV rebound in people after they have stopped ART. N-803 is 25 times more potent than its natural immune hormone counterpart, IL-15, which has known anti-HIV activity. Already approved for use in the treatment of bladder cancer, N-803 appears to stimulate both natural killer (NK) and T cells.

Dr. Peluso, who was a part of amfAR’s combination immunotherapy cure trial, will conduct a randomized clinical study of 18 people to test the ability of N-803 versus a placebo to suppress HIV following a planned treatment interruption. This approach has shown success in previous studies involving monkeys, but this will be the first trial to test the concept in humans.

Learning from Stem Cell Transplant Cures

As five cases have shown, transplants of stem cells missing CCR5, a co-receptor needed for HIV infection, can lead to an HIV cure. Two other individuals who received stem cell transplants using wildtype, or non-mutated, cells have also been cured. While stem cell transplants are too high-risk to work for everyone who needs a cure, the research has provided new insights about eradicating HIV.

With funding from amfAR in the amount of $479,249, Elena Herrera-Carrillo, PhD, of the Academic Medical Center of the University of Amsterdam in The Netherlands, is testing a CRISPR-Cas gene-editing approach to inactivate the CCR5 gene in people with HIV, which would bypass the need for a stem cell transplant. Rather than using defective HIV viruses or virus-like particles as vectors to deliver such gene editors, Dr. Herrera-Carrillo is working with lipid nanoparticles (LNPs), similar to the ones used in COVID-19 mRNA vaccines, to target both CCR5 and HIV. She has already designed LNPs capable of removing latent HIV from 95% of infected T cells in the test tube and now plans to extend this to a humanized mouse model of HIV infection.

Blood samples from people with HIV will be obtained through a collaboration in Uganda. In addition, and just as important to the future of HIV cure research, she will be training Ugandan scientists in her lab in Amsterdam to reproduce this technique and, if it shows promise, transfer that knowledge and related manufacturing processes to Africa.

Past amfAR grantee Jonah Sacha, PhD, of Oregon Health and Science University, will use new funding in the amount of $479,765 to continue to explore the role of allogeneic immunity in eradicating HIV.

The success of the “Geneva patient,” one of two transplant-based cures that involved wild-type donor cells, was not surprising to Dr. Sacha. Last year he reported that a monkey infected with simian-human immunodeficiency virus, treated with ART for a few months and then undergoing a stem cell transplant using a donor monkey with wild-type cells, appears to have been cured.

Dr. Sacha proposed that allogeneic immunity, or a graft-versus-host response—a key part of certain cancer cures following stem cell transplants using wild-type cells from donors—was involved and might be replicated without requiring an actual transplant.

Documenting what the target was in Dr. Sacha’s monkey experiments forms the basis of this new amfAR grant. He has preliminary data that it involves a “minor” antigen on white blood cells, and that administering killer CD8+ T cells trained on this target to SIV-infected monkeys would reproduce the effects of the transplant itself, opening the way for similar approaches in humans.

Click Here to read more from the December 2024 issue of amfAR INNOVATIONS.

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