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  • FAK Inhibitor 14 australia Despite these multiple mechanisms

    2022-06-15

    Despite these multiple mechanisms of viral persistence, one patient has been reportedly cured from HIV-1 infection . Timothy Brown, also known as the 'Berlin patient', was diagnosed with HIV-1 infection in 1995. After controlling viremia for several years via cART, he was diagnosed with acute myeloid leukemia and, in 2007 and 2008, received two allogeneic hematopoietic stem-cell transplants (allo-HSCT) from a human leukocyte antigen (HLA)-matched donor carrying a homozygous 32 nt deletion (Δ32) in the gene that encodes a coreceptor for HIV-1 viral entry. In later stages of infection, HIV-1 variants using other coreceptors, in particular CXCR4, can emerge. However, CCR5 is essential for HIV-1 to establish a persistent infection . The mutation, which is relatively frequent in Northern Europe, renders FAK Inhibitor 14 australia resistant to CCR5-tropic HIV-1 infection. The Berlin patient has remained off cART since the first day of his stem cell transplantation (SCT), in other words for 12 years. However, because of the complexity of the intervention, it is unclear which parameters were ultimately responsible for the elimination of the virus and the optimal resolution of infection. Recently, an HIV-1-infected adult in London underwent allo-HSCT treatment for Hodgkin’s lymphoma using cells from a / donor . CCR5-tropic, but not CXCR4-tropic viruses were identified in HIV-1 DNA from CD4T cells before transplantation. The host genotype was / and full chimerism with / cells was achieved after transplantation. cART was interrupted 16 months after SCT and no viral rebound has been observed 19 months after treatment interruption. Another patient in Düsseldorf who received allo-HSCT from a / donor has not shown viral rebound so far, 3 months since cART interruption . Comparison between the Berlin and London patients can help to better understand the mechanisms that have led to successful suppression of the virus. The Berlin patient is himself heterozygous for , and has been subjected to total body irradiation and strong conditioning with each HSCT, discontinuing cART immediately during the first HSCT . The case of the London patient indicated that a similar outcome could be achieved in / individuals after a single / allo-HSCT and mild conditioning, without total body irradiation or cART discontinuation during HSCT . By contrast, some degree of graft-versus-host reaction and early and sustained full donor chimerism in T cells was observed in both patients, and these may be important events associated with HIV clearing. The International Collaborative Consortium to Guide and Investigate the Potential for HIV Cure by Stem Cell Transplantation (ICISTEM, ) has assembled a large international cohort of HIV-positive individuals who have undergone allo-HSCT to treat diverse hematologic disorders. So far, 39 participants having received HSCT from matched or wild-type donors have been included in the cohort. This study has shown that allo-HSCT is unambiguously associated with a drastic reduction in the HIV reservoir, independently of engraftment with or wild-type cells (). In most cases, allo-HSCT in the presence of cART was followed by reduction of all virological markers to below detectable limits, possibly related to graft-versus-HIV reservoir-like effects . However, allo-HSCT is not a scalable therapy for HIV infection and also does not systematically lead to remission from infection, even when full donor chimerism is achieved. Recently, three individuals who had undergone allo-HSCT with cells from wild-type donors were reported to maintain undetectable viremia for 3–9 months following cART discontinuation before the virus FAK Inhibitor 14 australia reappeared , . Another HIV-1 infected adult (the 'Essen patient'), with anaplastic large-cell lymphoma, underwent SCT from a / donor . The virus rebounded 3 weeks after transplantation, and genotypic analyses of HIV-1 variants in this patient showed a shift from a dominantly CCR5-tropic HIV-1 before SCT towards variants that were independent of CCR5 usage (CXCR4-tropic HIV-1). These reports indicate that, despite the dramatic reduction of the HIV reservoir associated with allo-HSCT, the effect is not absolute, and very few remaining infected cells might result in (possibly delayed) but vigorous rebound of viremia, if no additional barrier exists to contain infection. The Berlin and London cases convincingly endorse the idea that full engraftment with / cells constitutes an effective block that favors remission from HIV infection upon allo-HSCT. Thus, a ‘kill and block’ approach to HIV infection seems to be required (). More than 22 000 homozygous donors have been identified so far in the context of the ICISTEM initiative, and these may help in the selection of suitable donors for HIV-infected individuals in need of allo-HSCT. Gene therapy approaches aimed at knocking out are also under study (). However, this raises the question of how best to prevent the risk of emergence of subdominant CXCR4 viruses (as was the case in the Essen patient). The role of immune responses may be crucial to durably control infection. Although it is still unclear how immune responses against HIV evolve following allo-HSCT, HIV-1 Gag-specific CD4 and CD8 T cell responses and HIV-1-specific antibodies seem to decrease following transplantation , . If some level of exposure to antigen occurred after transplantation, this appears to be insufficient to confer protection in allo-HCST recipients, and complementary immunotherapies may be needed in these individuals to achieve remission.