Infection with the human immunodeficiency virus type 1 (HIV-1) requires the presence of a CD4 receptor and a chemokine receptor, principally chemokine receptor 5 (CCR5). Homozygosity for a 32-bp deletion in the CCR5 allele provides resistance against HIV-1 acquisition. We transplanted stem cells from a donor who was homozygous for CCR5 delta32 in a patient with acute myeloid leukemia and HIV-1 infection. The patient remained without viral rebound 20 months after transplantation and discontinuation of antiretroviral therapy. This outcome demonstrates the critical role CCR5 plays in maintaining HIV-1 infection.

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...

There is intense interest in developing curative interventions for HIV. How such a cure will be quantified and defined is not known. We applied a series of measurements of HIV persistence to the study of an HIV-infected adult who has exhibited evidence of cure after allogeneic hematopoietic stem cell transplant from a homozygous CCR5Δ32 donor. Samples from blood, spinal fluid, lymph node, and gut were analyzed in multiple laboratories using different approaches. No HIV DNA or RNA was detected in peripheral blood mononuclear cells (PBMC), spinal fluid, lymph node, or terminal ileum, and no replication-competent virus could be cultured from PBMCs. However, HIV RNA was detected in plasma (2 laboratories) and HIV DNA was detected in the rectum (1 laboratory) at levels considerably lower than those expected in ART-suppressed patients. It was not possible to obtain sequence data from plasma or gut, while an X4 sequence from PBMC did not match the pre-transplant sequence. HIV antibody levels were readily detectable but declined over time; T cell responses were largely absent. The occasional, low-level PCR signals raise the possibility that some HIV nucleic acid might persist, although they could also be false positives. Since HIV levels in well-treated individuals are near the limits of detection of current assays, more sensitive assays need to be developed and validated. The absence of recrudescent HIV replication and waning HIV-specific immune responses five years after withdrawal of treatment provide proof of a clinical cure.

SummaryFor treatment of several malignancies, transplantation of allogeneic haematopoietic stem cells (HSCT) derived from bone marrow or peripheral blood has been used as a therapeutic procedure for decades. In the past, HSCT has been suggested as a treatment option for infection with the human immunodeficiency virus type 1 (HIV-1), but these attempts were mostly unsuccessful. Today, after the introduction of an active anti-retroviral therapy, the lifetime expectancy of HIV-infected patients has improved substantially, but nevertheless the incidence rate of malignancies in these patients has increased considerably. Therefore, it can be assumed that there will be a rising necessity for HIV-1-infected patients with malignancies for allogeneic HSCT. At the same time, there is increasing interest in treatment methods which might target the HIV-1 reservoir more effectively, and the question has been raised as to whether allogeneic HSCT could be linked to such strategies. In this paper the data of more than 25 years experience with allogeneic HSCT in patients with HIV-1 are reviewed and analysed.

Changes of the peripheral blood cell count in patients with AN is a frequent observation but the peripheral blood cell count cannot predict the severity of bone marrow atrophy. All hematological and morphological alterations disappear completely and rapidly after sufficient refeeding.

No abstract

No abstract

No abstract