Allo-SCT for hematological malignancies in the setting of HIV

Polizzotto, Mark N.; Skinner, Matthew J.; Cole‐Sinclair, Merrole; Opat, Stephen; Spencer, Andrew; Avery, Sharon

doi:10.1038/bmt.2009.168

Cited by 14 publications

(11 citation statements)

References 10 publications

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“…[12][13][14][15][16][17] For this reason, together with the fact that CXCR4-tropic HIV variants (X4 HIV) were present within the patient's pretransplantation HIV population, it was reasonable to hypothesize that HIV from the viral reservoir may reseed the body once the immune system has efficiently been restored with X4 HIV-susceptible target cells. 18,19 Accordingly, key questions that remain to be answered are (1) whether CD4 ϩ T cells have been efficiently restored throughout the body; (2) whether or not the patient's immune system includes HIV-susceptible target cells; and (3) how stable the size of the HIV reservoir is during the process of immune reconstitution after CCR5⌬32/⌬32 SCT.…”

Section: Introductionmentioning

confidence: 99%

Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation

Allers

Hütter

Hofmann

et al. 2011

Blood

646

474

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HIV entry into CD4 ؉ cells requires interaction with a cellular receptor, generally either CCR5 or CXCR4. We have previously reported the case of an HIV-infected patient in whom viral replication remained absent despite discontinuation of antiretroviral therapy after transplantation with CCR5⌬32/⌬32 stem cells. However, it was expected that the long-lived viral reservoir would lead to HIV rebound and disease progression during the process of immune reconstitution. In the present study, we demonstrate successful reconstitution of CD4 ؉ T cells at the systemic level as well as in the gut mucosal immune system after CCR5⌬32/⌬32 stem cell transplantation, while the patient remains without any sign of HIV infection. This was observed although recovered CD4 ؉ T cells contain a high proportion of activated memory CD4 ؉ T cells, ie, the preferential targets of HIV, and are suscep- IntroductionDestruction of the immune system by the HIV is driven by the loss of CD4 ϩ T cells in the peripheral blood and lymphoid tissues. Viral entry into CD4 ϩ cells is mediated by the interaction with a cellular chemokine receptor, the most common of which are CCR5 and CXCR4. 1 Because subsequent viral replication requires cellular gene expression processes, activated CD4 ϩ cells are the primary targets of productive HIV infection. Consequently, HIV infection leads predominantly to the depletion of activated memory CD4 ϩ T cells, most of which reside in the gastrointestinal (GI) mucosa. [2][3][4] Although therapeutic control of HIV replication allows the immune system to partially restore and delays disease progression, the cure of HIV infection remains still unachievable with use of the currently available antiretroviral drugs. The major barrier to viral eradication in patients receiving antiretroviral therapy (ART) is the establishment of HIV reservoirs, including low-level productively and latently infected cells. [5][6][7] Thus, maintenance of replicationcompetent HIV in long-lived cells and distinct anatomical sanctuaries allows the virus to reseed the body once ART is discontinued. 8 Cells of persons homozygous for the CCR5 gene variant ⌬32 (CCR5⌬32/⌬32) are naturally resistant to infection with CCR5-tropic HIV strains (R5 HIV) because of the lack of CCR5 cell-surface expression. 9 Previously, we demonstrated the feasibility of hematopoietic stem cell transplantation (SCT) with CCR5⌬32/ ⌬32 donor cells (CCR5⌬32/⌬32 SCT) in an HIV-infected patient with relapsed acute myeloid leukemia (AML) and documented absent viremia during the first 20 months of remission, during which time the patient did not receive ART. 10,11 This case clearly emphasizes the importance for continuing research in the field of CCR5-targeted treatment strategies, but uncertainty has remained over whether a cure for HIV infection has been achieved in this patient.In the setting of HIV infection, the effects of pretransplantation conditioning do not allow the complete elimination of HIV, as demonstrated by previous studies in which researchers demonstrated that HIV...

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Section: Introductionmentioning

confidence: 99%

Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation

Allers

Hütter

Hofmann

et al. 2011

Blood

646

474

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“…It is possible or even likely that the myeloablative therapy could have provided a synergistic effect. However, there are numerous reports of HIV-infected individuals undergoing allogeneic HSC or bone marrow transplants from donors not selected to be CCR5-negative, demonstrating that HIV-1 was not eliminated by the particular chemotherapy regimens used (Hassett et al 1983;Angelucci et al 1990;Bardini et al 1991;Schlegel et al 2000;Kang et al 2002;Avettand-Fenoel et al 2007;Wolf et al 2007;Woolfrey et al 2008;Kamp et al 2010;Polizzotto et al 2010), with one possible exception (Holland et al 1989). Of note, the Berlin patient's myeloablative therapy consisted of amsacrine, fludarabine, cytarabine, and cyclophosphamide, a regimen that has not previously been reported in patients with HIV infection.…”

Section: Hiv Latencymentioning

confidence: 99%

“…Of note, the Berlin patient's myeloablative therapy consisted of amsacrine, fludarabine, cytarabine, and cyclophosphamide, a regimen that has not previously been reported in patients with HIV infection. He was also treated with total body irradiation (TBI), both to enhance the antileukemic chemotherapy and for immunosuppression to facilitate engraftment; although historically, TBI used in conjunction with myeloblative therapy has not eradicated HIV (Giri et al 1992;Tomonari et al 2005;Polizzotto et al 2010). Of potential importance, the Berlin patient was also treated with several agents to prevent graft versus host disease, including antithymocyte globulin (ATG), cyclosporine, and mycophenolate mofetil, all of which have potent cytolytic or suppressive effects on T cells.…”

Section: Hiv Latencymentioning

confidence: 99%

Novel Cell and Gene Therapies for HIV

Hoxie

June

2012

Cold Spring Harbor Perspectives in Medicine

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“…Importantly, the allogeneic HSCT contributed to variable periods of antiretroviral-free HIV-1 remission, but viral reemergence took place despite a minimum 3-log 10 reduction in reservoir size. Considering the fact that the pretransplantation conditioning usually does not lead to the complete elimination of HIV [10,11,12], one possible explanation for the surprising result of Hütter's group [5 ]may be that the reconstituted immune system with CCR5 -deficient cells persistently suppresses the reactivation of viral replication from HIV reservoirs which have been greatly reduced by previous ablative regimens and ART. As a unique case, the Berlin patient should be considered a proof-of-concept, which has fueled the possibility of a cure for HIV.…”

mentioning

confidence: 99%

Possible Clues to a Functional Cure for HIV Infection

Lai¹

2015

Intervirology

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Allo-SCT for hematological malignancies in the setting of HIV

Cited by 14 publications

References 10 publications

Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation

Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation

Novel Cell and Gene Therapies for HIV

Possible Clues to a Functional Cure for HIV Infection

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