Comment HIV eradication: is cord blood the answer? Since the fi rst reported case of long-term HIV-1 remission CCR5 Δ32 heterozygous donor were used to bridge the after allogeneic haemopoeitc stem cell transplantation time during cord blood engraftment. The authors also (HSCT) in 2007, the search for an HIV cure has remained showed that engrafted cord-blood-derived cells were elusive. Timothy Ray Brown, the Berlin Patient, received resistant to the recipient’s HIV strain. donor cells homozygous for a 32 base-pair deletion in Despite the loss of detectable cell-associated HIV CCR5, rendering them resistant to his HIV-1 strain.1,2 DNA and RNA, low-level plasma viraemia was detected Subsequent studies showed that allogeneic HSCT with 76 days after transplant. The source of this very low- CCR5 wild-type donor cells can substantially reduce the level viraemia is unclear as the participant died from HIV reservoir, even to the point of being undetectable by progressive lymphoma and was unable to have an BSIP Astier/Science Photo Library BSIP sensitive laboratory assays.3–8 However, two individuals analytical treatment interruption, the only defi nitive Lancet HIV 2015 who had analytical antiretroviral treatment interruption test for permanent HIV remission or cure. Nonetheless, Published Online had viral rebound despite undetectable virus in blood residual recipient haemopoietic cell activation and May 20, 2015 or gut-associated lymphoid tissue years after wild-type death might have been the source of the residual low- http://dx.doi.org/10.1016/ S2352-3018(15)00088-0 6 HSCT. Substantially delayed times to viral rebound were level plasma viremia, because de novo infection of See Online/Articles observed, suggesting that HIV can persist in very few donor CCR5 Δ32 cells was unlikely. http://dx.doi.org/10.1016/ S2352-3018(15)00083-1 infected cells dispersed throughout tissue reservoirs.6 One striking observation from seven reported HIV- As a result, reduction in the reservoir size alone may be infected individuals that received CCR5 Δ32 donor HSCT insuffi cient to lead to permanent HIV remission in most is the high case-series mortality.11 Timothy Ray Brown is individuals. the only known HIV-infected individual living after CCR5 Several challenges remain in replicating the unique Δ32 homozygous transplant—all others died within a case of Timothy Ray Brown. For example, <1% of year of HSCT from transplant or tumour-related causes.11 individuals with northern European ancestry are The overall mortality rate for wild-type allogeneic HSCT homozygous for the CCR5 Δ32 variant, and prevalence in HIV-infected patients is 47% over 2 years.12 Although is lower in other ethnic groups. Given the need for the perceived high mortality rate in HIV-infected HLA-matched donor cells, the probability of fi nding an individuals that have had CCR5 Δ32 homozygous HSCT appropriate CCR5 donor remains very low. Furthermore, may simply be from sampling bias in a very limited many people with HIV have virus or mixtures of viral number of cases, questions arise as to the safety of variants able to use an alternative coreceptor for entry transplanting CCR5 Δ32 homozygous donor cells in the (CXCR4). For example, an individual who underwent HIV-infected population. Further studies involving HIV- allogeneic CCR5 Δ32 homozygous donor HSCT9 had infected individuals undergoing HSCT for malignant robust viral rebound with variants that use the CXCR4 diseases or clinical indications are therefore warranted. receptor shortly after transplantation. Clearly, allogeneic HSCT is not a practical curative The use of cord blood might increase the chances of strategy for most individuals with HIV. However, HSCT fi nding appropriate CCR5 Δ32 donor cells. In particular, is one of the few treatment approaches that leads to certain cord blood banks have the capacity to screen signifi cant reductions in virus reservoirs in individuals for the CCR5 Δ32 mutation, and cord blood transplant with established infection. Proof-of-concept studies, allows for a larger degree of HLA mismatch. In The such as those by Duarte and colleagues have the unique Lancet HIV, Duarte and colleagues10 present an example capacity to improve our scientifi c understanding of HIV of HSCT with CCR5 Δ32 homozygous cord-blood in persistence and provide much needed information to an HIV-1-infected individual with diff use large B-cell direct future, scalable eradication strategies. lymphoma. HIV DNA and RNA were readily detected in blood and gut-associated lymphoid tissue before HSCT, Timothy J Henrich but became undetectable in cells once full cord-blood Division of Infectious Diseases, Brigham and Women’s Hospital, donor chimerism was achieved after HSCT. This case Harvard Medical School, Boston, MA, USA [email protected] is unique in that cells from a third-party haploidentical www.thelancet.com/hiv Published online May 20, 2015 http://dx.doi.org/10.1016/S2352-3018(15)00088-0 1 Comment I declare no competing interests. 8 Kuball J, Kwon M, Wensing A, et al. Single cord blood transplantation combined with an HLA mismatched third party donor for high-risk 1 Allers K, Hutter G, Hofmann J, et al. Evidence for the cure of HIV infection haematological patients and HIV infection. Bone Marrow Transplant 2013; by CCR5Δ32/Δ32 stem cell transplantation. Blood 2011; 117: 2791–99. 48: S65–S66. 2 Hutter G, Nowak D, Mossner M, et al. Long-term control of HIV by CCR5 9 Kordelas L, Verheyen J, Beelen DW, et al. Shift of HIV tropism in stem-cell Delta32/Delta32 stem-cell transplantation. N Engl J Med 2009; transplantation with CCR5 Delta32 mutation. N Engl J Med 2014; 360: 692–98. 371: 880–82. 3 Avettand-Fenoel V, Mahlaoui N, Chaix ML, et al. Failure of bone marrow 10 Duarte RF, Salgado M, Sánchez-Ortega I, et al. CCR5 Δ32 homozygous cord transplantation to eradicate HIV reservoir despite effi cient HAART. blood allogeneic transplantation in a patient with HIV: a case report. AIDS 2007; 21: 776–77. Lancet HIV 2015; published online May 20. http://dx.doi.org/10.1016/ 4 Serrano D, Miralles P, Balsalobre P, et al. Graft-versus-tumor eff ect after S2352-3018(15)00083-1. allogeneic stem cell transplantation in HIV-positive patients with high-risk 11 Hutter G. More on shift of HIV tropism in stem-cell transplantation with hematologic malignancies. AIDS Res Hum Retroviruses 2013; 29: 1340–45. CCR5 delta32/delta32 mutation. N Engl J Med 2014; 371: 2437–38. 5 Woolfrey AE, Malhotra U, Harrington RD, et al. Generation of HIV-1-specifi c 12 Duarte RFF, Labopin M, Badoglio M, et al. Allogeneic transplantation in CD8+ cell responses following allogeneic hematopoietic cell patients with HIV-infection: a pair matched cohort study by the european transplantation. Blood 2008; 112: 3484–87. society for blood and marrow transplantation. Bone Marrow Transplant 6 Henrich TJ, Hanhauser E, Marty FM, et al. Antiretroviral-free HIV-1 2015; 50 (suppl 1): S5–S6. remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases. Ann Intern Med 2014; 161: 319–27. 7 Henrich TJ, Hu Z, Li JZ, et al. Long-term reduction in peripheral blood HIV type 1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation. J Infect Dis 2013; 207: 1694–702. 2 www.thelancet.com/hiv Published online May 20, 2015 http://dx.doi.org/10.1016/S2352-3018(15)00088-0.