Stem cell transplants can cure HIV

Resume: Researchers reveal that two non-human primates have been cured of Simian Immunodeficiency Virus (SIV), the monkey form of HIV, following a stem cell transplant.

The team identified two conditions that must coincide for a cure to occur and tracked the order in which HIV is cleared from the body. The insights could help develop a widespread cure for HIV, which affects about 38 million people worldwide.

Ultimately, scientists hope to make the cure more accessible and ideally deliver it through a single injection, rather than requiring a stem cell transplant.

Key Facts:

  1. The study found that a successful stem cell transplant can cure HIV, matching the five known cases of people cured of HIV through stem cell transplants.
  2. The researchers found that in order to effect a cure, transplanted donor stem cells must kill the recipient’s HIV-infected cells and prevent HIV from using the CCR5 receptor to infect donor cells.
  3. The team also documented the step-by-step way in which HIV is cleared from the body, starting with the blood circulating in the extremities, followed by lymph nodes in the extremities and abdomen.

Source: Oregon Health and Science University

New research from Oregon Health & Science University helps explain why at least five people became HIV-free after a stem cell transplant.

The insights from the study could move 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 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 conditions must coexist for healing to occur and documents the sequence in which HIV is cleared from the body – details that could help make this cure applicable to more people.

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

This shows a person's hands and the HIV virus structure.
The first known case of a cure for HIV through a stem cell transplant was reported in 2009. Credit: Neuroscience News

“This study helps us understand the mechanisms involved in bringing about that healing,” Sacha continued. “We hope our discoveries will help make this cure work for everyone, and ideally through a single injection rather than a stem cell transplant.”

The first known case of HIV cured by a stem cell transplant was reported in 2009. A man living with HIV was also diagnosed with acute myeloid leukemia, a cancer, and underwent a stem cell transplant in Berlin, Germany. Stem cell transplants, also called bone marrow transplants, are used to treat some cancers.

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. Four more people have been cured in the same way since the Berlin patient.

This study was conducted with a species of non-human primate known as Mauritian cynomolgus macaques, which the research team had previously shown can successfully receive stem cell transplants.

While all eight study subjects had HIV, four of them underwent transplants using stem cells from HIV-negative donors, and the other half served as study controls and went without transplants.

Of the four who received a transplant, two were cured of HIV after successfully treating graft versus host disease, commonly associated with stem cell transplants.

Other researchers have tried to cure non-human primates of HIV using similar methods, but this study marks the first time HIV-curing research animals have survived long-term.

Both remain alive today, approximately four years after transplantation, and are HIV-free. Sacha attributes their survival to exceptional care from veterinarians at the Oregon National Primate Research Center and the support of two study co-authors, OHSU clinicians 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 to preclinical macaque experiments to answer questions that would otherwise be nearly impossible, and also show 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

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

First, the transplanted donor stem cells helped kill the recipient’s HIV-infected cells 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 uncured test subjects, the virus managed to jump into the transplanted donor cells. A subsequent experiment confirmed that HIV could infect the donor cells as they attacked HIV. This led the researchers to determine that stopping HIV from using the CCR5 receptor to infect donor cells is also necessary to effect a cure.

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 circulating in their arms and legs.

Then they couldn’t find HIV in the lymph nodes, or clumps of immune tissue that contain white blood cells and fight infection. Lymph nodes in the extremities were the first to be HIV-free, followed by lymph nodes in the abdomen.

The step-by-step way the scientists watched HIV clear could help doctors evaluate the effectiveness of potential HIV treatments. For example, doctors could 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 discovered. Sacha hypothesizes that those patients may have had a small HIV reservoir in their abdominal lymph nodes that allowed the virus to persist and spread back through the body.

Sacha and colleagues continue to study the two non-human primates who have been cured of HIV. Next, they plan to dig deeper into their immune responses, including identifying any specific immune cells involved and which specific cells or molecules were targeted by the immune system.

financing: 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 the sole 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, monitors and manages relationships our researchers may have with entities outside OHSU.

With 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. Please review the details of OHSU’s Conflict of Interest Program to learn more about how we manage these business relationships.

All animal research 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 laboratory animals. 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 performed at OHSU without IACUC approval.

About this news about stem cell research

Author: Franky White
Source: Oregon Health and Science University
Contact: Franny White-Oregon Health and Science University
Image: The image is credited to Neuroscience News

Original research: Closed access.
“Allogeneic immunity clears latent virus after allogeneic stem cell transplantation in SIV-infected antiretroviral therapy-suppressed macaques” by Jonah Sacha et al. Immunity


Abstract

Allogeneic immunity clears latent virus after allogeneic stem cell transplantation in SIV-infected antiretroviral therapy-suppressed macaques

Highlights

  • Allogeneic immunity clears SIV reservoirs after allogeneic stem cell transplantation
  • Clearance of the SIV reservoir after transplantation occurs stepwise, first in the blood and then in the tissues
  • CCR5+ allogeneic HSCT can functionally cure SIV macaque monkeys
  • SIV spreads to CCR5+ donor cell transplantation despite complete suppressive therapy

Resume

Allogeneic hematopoietic stem cell transplantation (alloHSCT) from donors lacking CC chemokine receptor 5 (CCR5D32/D32) can cure HIV, but the mechanisms remain speculative.

To define how alloHSCT mediates HIV healing, we performed MHC-matched alloHSCT in SIV+anti-retroviral therapy (ART) suppressed Mauritian cynomolgus macaques (MCMs) and showed that allogeneic immunity was the main driver of reservoir clearance, occurring first in peripheral blood, then peripheral lymph nodes and finally in mesenteric lymph nodes draining the GI tract.

Although allogeneic immunity was able to eradicate the latent viral reservoir and did so in two alloHSCT-receiving MCMs that remained aviremic for more than 2.5 years after stopping ART, in other cases it was insufficient without protection of transplant cells from CCR5 deficiency, since CCR5 tropic virus spread to donor CD4+ T cells despite complete ART suppression.

These data demonstrate the individual contributions of allogeneic immunity and CCR5 deficiency to HIV healing and support defining targets of alloimmunity for curative strategies independent of HSCT.

Leave a comment