Promising stem cell research
By OREGON HEALTH & SCIENCE UNIVERSITY
The study found that two non-human primates were cured of a form
of HIV after stem cell transplantation, revealing that two factors must be
present for a cure – the donor stem cells attacking the HIV-infected cells and
preventing the virus from infecting the new cells.
New research unveils initial insights into the mechanisms
by which stem cell transplantation can eliminate the virus responsible for
AIDS.
New findings from Oregon Health &
Science University help explain how at least five
individuals have been cured of HIV following stem cell transplants. This
research paves the way toward the potential development of a widespread remedy
for the virus that results in AIDS, currently affecting
approximately 38 million people globally.
The study, which was published in the
journal Immunity, sheds light on how two nonhuman primates were
successfully treated for the monkey form of HIV through stem cell transplants.
It further reveals that a cure can only be achieved when two specific
conditions coincide and present the sequential process in which HIV is
eradicated from the body. These findings provide valuable insights that can
guide efforts to extend this curative strategy to a larger population.
“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 the 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.
Reference: “Allogeneic immunity clears latent
virus following allogeneic stem cell transplantation in SIV-infected
ART-suppressed macaques” by Helen L. Wu, Kathleen Busman-Sahay, Whitney C.
Weber, Courtney M. Waytashek, Carla D. Boyle, Katherine B. 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. Siliciano, Janet D.
Siliciano, Jacob D. Estes, Jeremy V. Smedley, Michael K. Axthelm, Gabrielle
Meyers, Richard T. Maziarz, Benjamin J. Burwitz, Jeffrey J. Stanton and Jonah
B. Sacha, 25 May 2023, Immunity.
DOI:
10.1016/j.immuni.2023.04.019
The study was funded by the National Institutes of Health, the Foundation for AIDS Research, and the Foundation
for AIDS Immune Research.
