Learning About “Known Unknowns” and “Unknown Unknowns” to Cure HIV

An allogeneic hematopoietic stem cell transplant (allo-HSCT) cured Timothy Ray Brown of HIV and cancer (1, 2). As he implied in the quote above, the mechanism responsible for his cure is a “known unknown.” The leading hypothesis is that immune reconstitution with cells from a donor with a mutated, nonfunctional CCR5 coreceptor for HIV played a major role. Curing HIV was previously considered impossible, and this success launched enormous research efforts using this and other strategies. A second case of cure after allo-HSCT has not yet been observed. However, advances have made it feasible to continue antiretroviral therapy (ART)–mediated suppression of HIV replication without impairing engraftment of allogeneic donor stem cells, leading to evaluations of potential HIV cure in patients receiving allo-HSCT with CCR5 wild-type donor cells under the cover of ART. Remarkably, reservoirs were depleted to an extent not seen with other interventions (3, 4). The most sensitive assays were unable to detect any replication-competent latent HIV after allo-HSCT during receipt of suppressive ART, although delayed rebound of HIV viremia was seen after ART was stopped in each case. Cure was not achieved, adding support for a contribution of the CCR5 mutated cells and adding more known unknowns to the HIV cure research agenda. How can estimation of reservoir size be improved to allow accurate prediction of whether cure is achievable before stopping ART? How are latent HIV reservoirs so radically depleted by allo-HSCT with CCR5 wild-type donor cells?