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A major obstacle to successful therapy and long-term control and cure of HIV has been the persistence of HIV in reservoirs that may contain latently infected, resting, and productively infected CD4+ T cells. Because of the long lifespan of these cells, the reservoir persists throughout the life of the infected individual.
Current therapies can inhibit ongoing viral replication, but they do not eliminate this long-lived reservoir. Thus, even after successful suppression of viral replication over many years with HAART, cessation of therapy invariably leads to rapid viral rebound and disease.
This reservoir of cells has shown to be extremely persistent, and the development of novel paradigm shifting approaches will likely be required for successful long-term control.
The Berlin Experiment
One such paradigm shifting approach was the report in 2008 by the Berlin group, demonstrating the functional cure of HIV by administration of high-dose chemotherapy followed by transplantation of HIV-resistant hematopoietic cells from an unrelated donor. While the procedure was performed to cure a hematologic malignancy, not to eliminate HIV, the results were compelling in that the patient was able to stop antiretroviral therapy without recurrence of readily detectable virus.
The unrelated donor cells were HIV resistant by virtue of homozygosity for the Δ32 mutation in the HIV co-receptor CCR5, which plays a critical role in the infectivity of HIV. Individuals homozygous for the CCR5Δ32 allele, in which deletion of a 32-bp segment results in a nonfunctional receptor for HIV, rarely become infected despite repeated high-risk exposures.
The so-called “Berlin experiment” provides important proof of principle that latent reservoirs of HIV can be eradicated using nontraditional methods. That said, the Berlin approach at present can not be used broadly for treating HIV, because CCR5Δ32 homozygous, HIV-resistant donor cells are very limited. An analysis performed at the Fred Hutchinson Cancer Research Center of 1273 donors determined that we will identify an HLA-matched HIV-resistant donor for only 0.1-0.4% of patients.
To make this highly promising treatment approach a reality for a much larger patient population, we propose here to make the patient’s own, autologous cells resistant to HIV infection, and thereby provide long-term cure—but without the toxicities associated with allogeneic HCT. By using autologous cells this treatment would in principle be available to every patient.
However, during autologous hematopoietic stem cell transplantation in HIV-infected individuals, between 105 and 1010 copies of HIV provirus are re-infused along with the graft, so means must also be found to inactivate HIV provirus within these cells.
Thus, the available data argue for the development of 1) strategies to modify CCR5 in autologous cells to make them HIV-resistant, and 2) strategies to eliminate functional provirus within infected cells.