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

Abstract

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...

Engineering HIV-Resistant, Anti-HIV Chimeric Antigen Receptor T Cells

“…36,37 Individuals with an allelic variant that is not functional (CCR5D32) are protected from CCR5-tropic HIV infection. 38 Hematopoietic stem cell transplant using a CCR5D32 donor led to the only known cure of HIV-1 infection, 39,40 and T cells treated with engineered nucleases that introduce mutations at the CCR5 locus are resistant to HIV, [41][42][43][44][45] accelerating ongoing efforts to develop gene editing-and cell-based therapeutic agents for HIV. 11,46 Using new gene-editing techniques, it has recently become possible to achieve high rates of homology-directed recombination (HDR) of therapeutic cassettes into targeted loci, including CCR5 in primary T cells.…”

Human population structure and the adaptive response to pathogen-induced selection pressures

“…As an example, the CCR5-D32 allele (explained further below), which confers resistance to HIV in homozygous carriers [9][10][11][12][13], is now forming the basis of trial therapies based on stem cell transplantation. A recent paper [14] reports on an infected patient who received blood stem cells from a D32/D32 homozygous donor. After transplantation, this patient reconstituted his T cells to normal levels, and HIV viral levels were undetectable despite the patient not taking anti-retroviral therapies for a period of more than 3.5 years.…”

HIV/AIDS: 30 Years of progress and future challenges

“…However, recent reports on the HIV-infected 'Berlin patient' who received, for his leukemia, a heterologous BM stem cell transplant from a CCR5 À donor have been encouraging. For over 5 years this patient has been free of any sign of HIV in lymphoid and mucosal tissues [95]. Considered a 'functional cure', researchers are examining approaches to mimic this promising result.…”