A new study reveals the first details about how stem cell transplantation can kill the virus that causes AIDS

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Published today in the magazine Immunity, the OHSU-led study describes how two non-human primates were cured of the monkey form of HIV after receiving a stem cell transplant. It also reveals that two circumstances must coexist for a cure to occur, and documents the order in which HIV is cleared from the body, details that may inform efforts to make this cure applicable to more people.

“Five patients have already shown that HIV can be cured,” said the study’s principal investigator, Jonah Sacha, Ph.D., a professor at the OHSU National Primate Research Center and Vaccine and Gene Therapy Institute in Oregon.

“This study is helping us focus on the mechanisms involved in making that cure happen,” Sacha continued. “We hope that our discoveries will help make this cure work for anyone, and ideally through a single injection rather than a stem cell transplant.”

The first known case of a cure for HIV through a stem cell transplant was reported in 2009. A man living with HIV was also diagnosed with acute myeloid leukemia, a type of cancer, and underwent a stem cell transplant in Berlin Germany. Stem cell transplants, also called bone marrow transplants, are used to treat some forms of cancer. Known as the Berlin patient, he received donated stem cells from someone with a mutated CCR5 gene, which normally encodes a receptor on the surface of white blood cells that HIV uses to infect new cells. A CCR5 mutation makes it harder for the virus to infect cells and can make people resistant to HIV. Since the Berlin patient, four more people have been similarly cured.

This study was conducted with a species of non-human primate known as the Mauritian cynomolgus macaque, which the research team previously demonstrated can successfully receive stem cell transplants. Although all eight study subjects had HIV, four of them underwent stem cell transplants from HIV-negative donors, and the other half served as study controls and received no transplants.

Of the four who received transplants, two were cured of HIV after being successfully treated for graft-versus-host disease, which is commonly associated with stem cell transplants.

Other researchers have tried to cure HIV in non-human primates using similar methods, but this study marks the first time that research animals cured of HIV have survived long-term. Both are still alive and free of HIV today, some four years after the transplant. Sacha credits his survival to the exceptional care of veterinarians at the Oregon National Primate Research Center and the support of two study co-authors, OHSU physicians who care for people undergoing stem cell transplants: Richard T. Maziarz, MD, and Gabrielle Meyers, MD

“These results highlight the power of linking human clinical studies with preclinical experiments in macaques to answer questions that would be nearly impossible to ask otherwise, as well as demonstrate a way forward to cure human diseases,” said Maziarz, professor of medicine at the OHSU School of Medicine and medical director of the adult blood and marrow stem cell transplant and cell therapy programs at the OHSU Knight Cancer Institute.

The how behind the cure

Although Sacha said it was gratifying to confirm that stem cell transplantation cured nonhuman primates, he and his fellow scientists also wanted to understand how it worked. While evaluating the samples from the subjects, the scientists determined that there were two different, but equally important ways to defeat HIV.

First, the transplanted donor stem cells helped kill HIV-infected cells in recipients by recognizing them as foreign invaders and attacking them, similar to the graft-versus-leukemia process that can cure people of cancer.

Second, in the two subjects who were not cured, the virus managed to jump into the cells of the transplanted donor. A later experiment verified that HIV could infect donor cells while attacking HIV. This led the researchers to determine that preventing HIV from using the CCR5 receptor to infect donor cells is also necessary for a cure to occur.

The researchers also found that HIV was cleared from the subjects’ bodies in a series of steps. First, the scientists saw that HIV was no longer detectable in the blood that circulated through his arms and legs. Then they couldn’t find HIV in the lymph nodes or in the clumps of immune tissue that contain white blood cells that fight infection. Lymph nodes in the extremities were the first to be free of HIV, followed by lymph nodes in the abdomen.

The gradual way in which scientists observed HIV being eliminated could help doctors assess the effectiveness of possible HIV cures. For example, doctors might focus on analyzing blood collected from both peripheral veins and lymph nodes. This knowledge may also help explain why some transplant patients initially appeared to be cured, but HIV was later detected. Sacha hypothesizes that those patients may have had a small reservoir of HIV in their abdominal lymph nodes that allowed the virus to persist and spread again throughout the body.

Sacha and his colleagues continue to study the two non-human primates cured of HIV. Next, they plan to delve into their immune responses, including identifying all the specific immune cells involved and which specific cells or molecules were attacked by the immune system.

This research is supported by the National Institutes of Health (grants AI112433, AI129703, P51 OD011092) and the Foundation for AIDS Research (grant 108832) and the Foundation for AIDS Immune Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

In our interest to ensure the integrity of our research and as part of our commitment to public transparency, OHSU actively regulates, tracks, and manages the relationships our researchers may have with entities outside of OHSU. In connection with this research, Dr. Sacha has a significant financial interest in CytoDyn, a company that may have a commercial interest in the results of this research and technology. Please review the OHSU Conflict of Interest Program details for more information on how we manage these business relationships.

All research involving animals 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 people who work with animals. No work with live animals can be performed at OHSU without IACUC approval.

REFERENCE: Helen Wu, Kathleen Busman-Sahay, Whitney C. Weber, Courtney M. Waytashek, Carla D. Boyle, Katherine Bateman, Jason S. Reed, Joseph M. Hwang, Christine Shriver-Munsch, Tonya Swanson, Mina Northrup, Kimberly Armantrout, Heidi Price, Mitch Robertson-LeVay, Samantha Uttke, Mithra R. Kumar, Emily J. Fray, Sol Taylor-Brill, Stephen Bondoc, Rebecca Agnor, Stephanie L. Junell, Alfred W. Legasse, Cassandra Moats, Rachele M. Bochart, Joseph Sciurba, Benjamin N. Bimber, Michelle N. Sullivan, Brandy Dozier, Rhonda P. MacAllister, Theodore R. Hobbs, Lauren D. Martin, Angela Panoskaltsis-Mortari, Lois MA Colgin, Robert F. Silciano, Janet D. Silciano, Jacob D. Estes, Jeremy V. Smedly, Michael K. Axthelm, Gabrielle Meyers, Richard T. Maziarz, Benjamin J. Burwitz, Jeffrey J. Stanton, Jonah B. Sacha, Allogeneic immunity clears latent virus after transplantation Allogeneic Stem Cell Analysis in Antiretroviral-Deleted Macaques Infected with SIV, Immunity, May 25, 2023, DOI: 10.1016/j.immuni.2023.04.019.