Research offers clues for potential widespread HIV cure in people
New study reveals first details on how stem cell transplantation can kill virus that causes AIDS
Peer-Reviewed PublicationPORTLAND, Oregon -- New research from Oregon Health & Science University is helping explain why at least five people have become HIV-free after receiving a stem cell transplant. The study’s insights may bring scientists closer to developing what they hope will become a widespread cure for the virus that causes AIDS, which has infected about 38 million people worldwide.
Published today in the journal Immunity, the OHSU-led study describes how two nonhuman primates were cured of the monkey form of HIV after receiving a stem cell transplant. It also reveals that two circumstances must co-exist for a cure to occur and documents the order in which HIV is cleared from the body — details that can inform efforts to make this cure applicable to more people.
“Five patients have already demonstrated that HIV can be cured,” said the study’s lead researcher, Jonah Sacha, Ph.D., a professor at OHSU’s Oregon National Primate Research Center and Vaccine and Gene Therapy Institute.
“This study is helping us home in on the mechanisms involved in making that cure happen,” Sacha continued. “We hope our discoveries will help to make this cure work for anyone, and ideally through a single injection instead of a stem cell transplant.”
The first known case of HIV being cured through a stem cell transplant was reported in 2009. A man who was 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, which are 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 codes for a receptor on the surface of white blood cells that HIV uses to infect new cells. A CCR5 mutation makes it difficult 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 nonhuman primate known as Mauritian cynomolgus macaques, which the research team previously demonstrated can successfully receive stem cell transplants. While all of the study’s eight subjects had HIV, four of them underwent a transplant with stem cells from HIV-negative donors, and the other half served as the study’s controls and went without transplants.
Of the four that received transplants, two were cured of HIV after successfully being treated for graft-versus-host disease, which is commonly associated with stem cell transplants.
Other researchers have tried to cure nonhuman primates of HIV using similar methods, but this study marks the first time that HIV-cured research animals have survived long term. Both remain alive and HIV-free today, about four years after transplantation. Sacha attributes their survival to exceptional care from Oregon National Primate Research Center veterinarians and the support of two study coauthors, OHSU clinicians who care for people who undergo stem cell transplants: Richard T. Maziarz, M.D., and Gabrielle Meyers, M.D.
“These results highlight the power of linking human clinical studies with pre-clinical macaque experiments to answer questions that would be almost impossible to do otherwise, as well as demonstrate a path forward to curing human disease,” said Maziarz, a professor of medicine in the OHSU School of Medicine and medical director of the adult blood and marrow stem cell transplant and cellular therapy programs in the OHSU Knight Cancer Institute.
The how behind the cure
Although Sacha said it was gratifying to confirm stem cell transplantation cured the nonhuman primates, he and his fellow scientists also wanted to understand how it worked. While evaluating samples from the subjects, the scientists determined there were two different, but equally important, ways they beat HIV.
First, the transplanted donor stem cells helped kill the recipients’ HIV-infected cells by recognizing them as foreign invaders and attacking them, similar to the process of graft-versus-leukemia that can cure people of cancer.
Second, in the two subjects that were not cured, the virus managed to jump into the transplanted donor cells. A subsequent experiment verified that HIV was able to infect the donor cells while they were attacking HIV. This led the researchers to determine that stopping HIV from using the CCR5 receptor to infect donor cells is also needed for a cure to occur.
The researchers also discovered that HIV was cleared from the subjects’ bodies in a series of steps. First, the scientists saw that HIV was no longer detectable in blood circulating in their arms and legs. Next, they couldn’t find HIV in lymph nodes, or lumps of immune tissue that contain white blood cells and fight infection. Lymph nodes in the limbs were the first to be HIV-free, followed by lymph nodes in the abdomen.
The step-wise fashion by which the scientists observed HIV being cleared could help physicians as they evaluate the effectiveness of potential HIV cures. For example, clinicians could focus on analyzing blood collected from both peripheral veins and lymph nodes. This knowledge may also help explain why some patients who have received transplants initially have 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 enabled the virus to persist and spread again throughout the body.
Sacha and colleagues continue to study the two nonhuman primates cured of HIV. Next, they plan to dig deeper into their immune responses, including identifying all of the specific immune cells involved and which specific cells or molecules were targeted 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 of ensuring the integrity of our research and as part of our commitment to public transparency, OHSU actively regulates, tracks and manages relationships that our researchers may hold with entities outside of OHSU. In regard to 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. Review details of OHSU's conflict of interest program to find out more about how we manage these business relationships.
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. No live animal work may be conducted 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 M.A. 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 following allogenic stem cell transplantation in SIV-infected antiretroviral therapy-suppressed macaques, Immunity, May 25, 2023, DOI: 10.1016/j.immuni.2023.04.019.
Photos:
Portraits of Jonah Sacha, Ph.D.: https://news.ohsu.edu/search?q=Jonah+Sacha&year=&c=&s=-date&ct=photo
Richard Maziarz, M.D.: https://news.ohsu.edu/file?fid=5b4e33b72cfac24287c41421
Related OHSU News stories:
Understanding the Berlin patient’s unexpected cure (Nov. 10, 2017)
One-time gene therapy injection could provide HIV treatment that may last a lifetime (July 8, 2022)
OHSU-developed HIV vaccine tech tested in humans for first time (Jan. 6, 2021)
International project seeks to eliminate HIV in kids (Sept. 13, 2021)
Links:
JOURNAL
Immunity
METHOD OF RESEARCH
Experimental study
SUBJECT OF RESEARCH
Animals
ARTICLE TITLE
Allogeneic immunity clears latent virus following allogenic stem cell transplantation in SIV-infected antiretroviral therapy-suppressed macaques
ARTICLE PUBLICATION DATE
25-May-2023
COI STATEMENT
Jonah Sacha, Ph.D., has a significant financial interest in CytoDyn, a company that may have a commercial interest in the results of this research and technology.
HIV drugs may help fight deadly fungal infection, Center for One Health Research study finds
IMAGE: (FROM LEFT) EHAB SALAMA AND YEHIA ELGAMMAL WORK IN MOHAMED SELEEM’S LAB AT THE CENTER FOR ONE HEALTH RESEARCH. PHOTO BY ANDREW MANN FOR VIRGINIA TECH. view more
CREDIT: VIRGINIA TECH
Antiviral drugs can make antifungals work again.
That, at its simplest, is the approach Mohamed Seleem’s lab at the Center for One Health Research has found may be a key treatment strategy in the battle against Candida auris, a frighteningly deadly fungal pathogen discovered in 2009 that is considered an urgent threat by the Centers for Disease Control and Prevention (CDC).
Candida auris, first discovered in Japan as an ear infection, has a staggering 60 percent mortality rate among those it infects, primarily people with compromised health in hospitals and nursing homes.
Recently, Seleem and Ph.D. students Yehia Elgammal and Ehab A. Salama published a paper in the American Society for Microbiology’s Antimicrobial Agents and Chemotherapy journal detailing the potential use of atazanavir, an HIV protease inhibitor drug, as a new avenue to improving the effectiveness of existing antifungals for those with a Candida auris infection.
A perfect storm of antimicrobial resistance, global warming and the COVID-19 pandemic has resulted in the rapid spread of Candida auris around the world, said Seleem, director of the center, a collaboration between the Virginia-Maryland College of Veterinary Medicine and the Edward Via College of Osteopathic Medicine.
“We don't have lots of drugs to use to treat fungal pathogens. We have only three classes of antifungal drugs,” said Seleem, the Tyler J. and Frances F. Young Chair in Bacteriology at Virginia Tech. “With a fungal pathogen, it’s often resistant to one class, but then we have two other options. What's scary about Candida auris is it shows resistance to all three classes of the antifungal.
“The CDC has a list of urgent threats, but on that list there is just one fungal pathogen, which is Candida auris. Because it's urgent, we need to deal with it.”
Widespread use of fungicides in agriculture, in addition to the three classes of antifungal drugs used widely in medicine, has contributed to fungal pathogens developing more resistance, particularly Candida auris.
Also, its rise has been linked to rising global temperatures and to easier spread through hospitals filled with COVID-19 patients in recent years during the global pandemic.
Atazanavir, an HIV protease inhibitor drug, has been found by Seleem’s lab to block the ability of Candida auris to excrete antifungals through its efflux pumps.
Think of a boat taking on water and hoses siphoning that water out of the boat to keep it afloat. Atazanavir stops up the hoses.
That allows the azole class of antifungal drugs to not be expelled as easily and perform better against Candida auris, the Seleem lab’s research has found.
The research on atazanavir builds on work three years ago by Seleem’s lab, then at Purdue University, finding potentially similar benefit in lopinavir, another HIV protease inhibitor.
HIV protease drugs are already in wide use among HIV patients, who can also be extra susceptible to Candida auris. Some HIV patients have likely been taking HIV protease drugs and azole-class antifungals in tandem for separate purposes, providing a potential source of already existing data that can be reviewed on whether those patients had Candida auris and what effects the emerging pathogen had on them.
Repurposing drugs already on the market for new uses can allow those treatments to reach widespread clinical use much more rapidly than would happen with the discovery of an entirely new drug, as existing drugs have already been tested and approved by the Food and Drug Administration and have years of further observation of effects in prescriptive use.
JOURNAL
Antimicrobial Agents and Chemotherapy
