The new case of long-term HIV remission was reported on Feb. 15 at the 29th annual Conference on Retroviruses and Opportunistic Infections, in Denver.

The patient received transplants of blood- and immune-cell replenishing stem cells after having her own blood cell population, including leukemic cells, destroyed by high-dose chemotherapy. The transplanted cells came from two sources: stem cells from a healthy adult relative were used to quickly restore her blood cell population to reduce infectious complications, and umbilical cord blood from an unrelated newborn child was used to provide long-term blood reconstitution.

Cord blood is used to supply blood stem cells for transplants for patients unable to find matched adult donors. Transplant specialists have found that cord blood may be used successfully even when they come from an unrelated donor whose immune markers only partially match the recipient’s.

Doctors in this case used cord blood containing an HIV-resistance gene variant called CCR5Δ32. HIV normally uses the CCR5 co-receptor to help it infect immune cells, but the receptor’s Δ32 variant effectively blocks viral entry.

Three months after the transplant, tests showed that the patient’s blood cell population was entirely derived from the HIV-resistant cord blood cells. Post-transplant studies could no longer detect HIV by various sensitive assays. The patient eventually stopped taking antiretroviral drugs to suppress her HIV infection, and so far, has been off the HIV drugs for 14 months, with no signs of HIV re-emergence after close follow-up during COVID 19 pandemic—indicating a likely cure, although physicians at this stage prefer to call it long-term remission. She has also been leukemia-free for more than four years.

Two prior cases of long-term remission in HIV-positive cancer patients after adult CCR5Δ32 stem cell transplantation have been reported. This case is the first to use cord blood cells, and the first to treat a woman and someone who identifies as mixed-race. Since the CCR5Δ32 variant is much more common in people of European heritage, it is harder to find well-matched CCR5Δ32 donors for traditional stem cell transplants into nonwhite patients, although the use of cord blood partly alleviates this problem.

Stem cell transplant specialists Dr. Jingmei Hsu and Dr. Koen Van Besien and infectious disease specialist Dr. Marshall Glesby were the physician-scientists who led the NIH-funded clinical trial at Weill Cornell Medicine in collaboration with investigators at University of California Los Angeles, Johns Hopkins University School of Medicine and several other institutions.

The investigators concluded that cord blood containing the CCR5Δ32 variant offers a possible cure for both hematological malignancies and HIV and should be considered as a stem cell source when HIV-positive cancer patients need blood stem cell transplants. However, the procedure is considered too risky for HIV-positive patients who otherwise don’t need such transplants.

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborations with external organizations to foster scientific innovation and provide expert guidance. Weill Cornell Medicine and its faculty make this information available to the public to ensure transparency. External relationship information is available on the faculty profiles of Dr. Jingmei Hsu, Dr. Koen Van Besien, and Dr. Marshall Glesby.

MSCs are found in bone marrow, and are “multipotent,” meaning that they can both renew themselves and develop into a variety of specialized cell types, such as bone, fat, and cartilage cells. The researchers had previously developed a mouse line that uses green fluorescent protein to highlight cells expressing a particular molecule known as CD73. Studies of the bone marrow in this mouse revealed that a subpopulation of MSCs expressed CD73, as well as the sinusoidal endothelial cells (sECs) that are part of the vascular system of the bone marrow.

The CD73-positive MSCs could be seen to proliferate more than the CD73- negative MSCs, and to have a higher potential to differentiate into different cell types, indicating that this group of MSCs may be particularly effective for bone repair. The researchers therefore went on to study the functions of these CD73-positive MSCs in fracture healing.

As a fracture heals, it progresses through various stages. These include clotted blood forming at the fracture, which becomes replaced by a callus of fibrous tissues and cartilage, followed by formation of a hard bony callus. The bone is then remodeled, as regular bone replaces the hard callus and the bone returns to its usual shape.

“The generation of the callus is critically dependent on the recruitment of MSCs from the surrounding tissue and the bone marrow,” explains lead author Assistant Professor Kenichi Kimura. “Therefore, fracture healing models are helpful for exploring the cellular dynamics of MSC migration and differentiation during tissue regeneration.”

The team was able to observe the CD73-positive MSCs moving towards the site of the fracture and forming new cartilage and bone cells to heal the fracture. The CD73-positive sECs were also involved in the healing of the fracture, as they contributed to the process of “neovascularization,” the formation of new blood vessels to support the healed bone.

Finally, they went on to graft CD73-positive MSCs into the area of a fracture, which markedly enhanced the healing process compared with when they grafted into CD73-negative MSCs.

Says Assistant Professor Kimura, “The identification of this subpopulation of MSCs could be of great benefit for regenerative medicine and the treatment of fractures.”

Journal Reference:

1. Kenichi Kimura, Martin Breitbach, Frank A. Schildberg, Michael Hesse, Bernd K. Fleischmann. Bone marrow CD73 mesenchymal stem cells display increased stemness in vitro and promote fracture healing in vivo. Bone Reports, 2021; 15: 101133 DOI: 1016/j.bonr.2021.101133