In the November 20, 2018 issue of the Annals of Internal Medicine, an editorial titled, “Learning ‘Known Unknowns’ and ‘Unknown Unknowns’ to Cure HIV” was written by Dr. D’Aquila, director of the Third Coast CFAR and an NIH-funded program project aimed at learning how to achieve a sustained remission of HIV after stopping antiretroviral therapy (ART). The editorial pertains to the high-priority (and so far unsuccessful) efforts to replicate the cure of HIV in only a single person, Timothy Ray Brown. This cure, defined as lack of rebound HIV viremia after stopping ART, followed a stem cell transplant (for treatment of a cancer) with another person’s cells that lacked a working receptor, CCR5, that HIV needs to enter its target cells. Donors with such CCR5-mutated cells are rare. The lack of that HIV entry receptor on CCR5-mutated cells is felt to be the main contributor to Mr. Brown’s cure, but there are other possible contributing mechanisms.
D’Aquila’s editorial presents a perspective on an original report in the November 20 Annals issue which describes the largest number of HIV-infected patients with concomitant hematologic diseases who received stem cell transplants with CCR5 wild-type donor cells (with a functioning receptor HIV can use) than in any published study to date (1). In this report and the smaller studies reported previously, it was observed that the “latent reservoir cells” harboring HIV that can reactivate after ART is stopped were depleted to very low levels after transplant. This new report finds that almost all recipients had markedly reduced reservoirs and makes a correlation for the first time with a “graft-versus-HIV-reservoir” effect of the donor cells and depletion of the recipient’s HIV reservoir cells. This suggests that some cells with latent HIV may have been killed along with uninfected recipient cells by donor cells recognizing “non-self” cellular components. The editorial points out that only a small fraction of other HIV-infected, ART-suppressed persons have such reservoir reduction and suggests that future research carefully pausing ART in HIV-infected recipients of stem cell transplants with CCR5-wild type donor cells may be informative about the ‘unknown unknowns’ that could limit viremia rebound off-ART. The long-term goal is to help achieve remissions off-ART in the small number of such transplant recipients and maybe even a broader range of ART-suppressed patients.
- Salgado M, Kwon M, Galvez C, Badiola J, Nijhuis M, Bandera A, et al. Mechanisms that contribute to a profound reduction of the HIV-1 reservoir after allogeneic stem cell transplant. Ann Intern Med. 2018;169:674-83. doi:10.7326/M18-0759