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In-depth virological and immunological characterization of HIV-1 cure after CCR5Δ32/Δ32 allogeneic hematopoietic stem cell transplantation
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Nature Feb 20 2023
Abstract
Despite scientific evidence originating from two patients published to date that CCR5Δ32/Δ32 hematopoietic stem cell transplantation (HSCT) can cure human immunodeficiency virus type 1 (HIV-1), the knowledge of immunological and virological correlates of cure is limited. Here we characterize a case of long-term HIV-1 remission of a 53-year-old male who was carefully monitored for more than 9 years after allogeneic CCR5Δ32/Δ32 HSCT performed for acute myeloid leukemia. Despite sporadic traces of HIV-1 DNA detected by droplet digital PCR and in situ hybridization assays in peripheral T cell subsets and tissue-derived samples, repeated ex vivo quantitative and in vivo outgrowth assays in humanized mice did not reveal replication-competent virus. Low levels of immune activation and waning HIV-1-specific humoral and cellular immune responses indicated a lack of ongoing antigen production. Four years after analytical treatment interruption, the absence of a viral rebound and the lack of immunological correlates of HIV-1 antigen persistence are strong evidence for HIV-1 cure after CCR5Δ32/Δ32 HSCT.
excerpt....
Human immunodeficiency virus type 1 (HIV-1) persists in the body during antiretroviral therapy (ART) in latently infected CD4+ T cells, but allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to substantially reduce the viral reservoir1,2. However, some of the reservoir-harboring immune cells are extremely long-lived3, partially resistant to chemotherapy regimens used during HSCT procedures and can cause viral rebound on analytical treatment interruption (ATI)4,5. Notably, both cases of successful HIV-1 cure published so far-the 'London patient' (IciStem no. 36) and the 'Berlin patient'-received a CCR5Δ32/Δ32 allograft6,7 conferring extended resistance to HIV-1 due to the absence of surface expression of the CCR5 coreceptor.
In this study, we provide a detailed longitudinal virological and in-depth immunological analysis of the peripheral blood and tissue compartments of a 53-year-old male patient (IciStem no. 19)8, alive and in good health 117 months after CCR5Δ32/Δ32 allogeneic HSCT and 48 months after ATI. The patient was diagnosed to be HIV-1 clade B positive in January 2008 and presented with a CD4+ T cell count of 964 cells per μl and an HIV-1 plasma viral load of 12,850 copies per ml (Centers for Disease Control and Prevention A1, which was no indication for initiation of ART according to the national guidelines at that time). In October 2010, an ART regimen with tenofovir disoproxil fumarate (TDF), emtricitabine (FTC) and darunavir and ritonavir (DRV/r) was initiated (503 CD4+ T cells per μl and 35,303 HIV-1 copies per ml), resulting in a continuously suppressed plasma viral load (Fig. 1a). In January 2011, the patient was diagnosed with acute myeloid leukemia (AML) M2 according to the French-American-British classification, which carried an inversion of chromosome 16 at p13q22, resulting in the CBFB-MYH11 fusion protein. The patient achieved hematological complete remission after chemotherapy, which included idarubicin, cytarabine, etoposide induction therapy and three high-dose cytarabine (HiDAC) consolidation cycles. To avoid drug-drug interactions, DRV/r was switched to raltegravir in March 2011.
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