HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation

• Published in: Nature (London) Vol. 568; no. 7751; pp. 244 - 248
• Main Authors: Gupta, Ravindra K., Abdul-Jawad, Sultan, McCoy, Laura E., Mok, Hoi Ping, Peppa, Dimitra, Salgado, Maria, Martinez-Picado, Javier, Nijhuis, Monique, Wensing, Annemarie M. J., Lee, Helen, Grant, Paul, Nastouli, Eleni, Lambert, Jonathan, Pace, Matthew, Salasc, Fanny, Monit, Christopher, Innes, Andrew J., Muir, Luke, Waters, Laura, Frater, John, Lever, Andrew M. L., Edwards, Simon G., Gabriel, Ian H., Olavarria, Eduardo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.04.2019; Nature Publishing Group
• Subjects: 13; 13/1; 13/31; 45/23; 45/91; 631/326/596/1787; 631/67/1990/291/1556; Acute myeloid leukemia; Antibodies; Antiretroviral agents; Antiretroviral drugs; Antiretroviral therapy; Bioinformatics; CCR5 protein; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; Chemotherapy; CXCR4 protein; Cytomegalovirus; Cytomegalovirus - chemistry; Cytomegalovirus - immunology; Deoxyribonucleic acid; DNA; Drug resistance; Drug therapy; gag Gene Products, Human Immunodeficiency Virus - immunology; Gag protein; Graft-versus-host reaction; Hematopoietic Stem Cell Transplantation - methods; Hematopoietic stem cells; HIV; HIV Antibodies - immunology; HIV Infections - complications; HIV Infections - therapy; HIV Infections - virology; HIV-1 - chemistry; HIV-1 - immunology; Hodgkin Disease - complications; Hodgkin Disease - drug therapy; Hodgkin's lymphoma; Human immunodeficiency virus; Humanities and Social Sciences; Humans; Infections; Irradiation; Letter; Leukemia; Lymphocytes; Lymphocytes T; Lymphoma; multidisciplinary; Mutation; Patients; Peripheral blood; Radiation; Receptors, CCR5 - chemistry; Receptors, CCR5 - deficiency; Receptors, CCR5 - genetics; Receptors, CCR5 - metabolism; Receptors, CXCR4 - metabolism; Remission; Remission (Medicine); Ribonucleic acid; RNA; Science; Science (multidisciplinary); Stem cell transplantation; Stem cells; Transplantation; Transplantation, Homologous; Transplants & implants; Viruses
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-1027-4

A cure for HIV-1 remains unattainable as only one case has been reported, a decade ago 1 , 2 . The individual—who is known as the ‘Berlin patient’—underwent two allogeneic haematopoietic stem-cell transplantation (HSCT) procedures using a donor with a homozygous mutation in the HIV coreceptor CCR5 (CCR5Δ32/Δ32) to treat his acute myeloid leukaemia. Total body irradiation was given with each HSCT. Notably, it is unclear which treatment or patient parameters contributed to this case of long-term HIV remission. Here we show that HIV-1 remission may be possible with a less aggressive and toxic approach. An adult infected with HIV-1 underwent allogeneic HSCT for Hodgkin’s lymphoma using cells from a CCR5Δ32/Δ32 donor. He experienced mild gut graft-versus-host disease. Antiretroviral therapy was interrupted 16 months after transplantation. HIV-1 remission has been maintained over a further 18 months. Plasma HIV-1 RNA has been undetectable at less than one copy per millilitre along with undetectable HIV-1 DNA in peripheral CD4 T lymphocytes. Quantitative viral outgrowth assays from peripheral CD4 T lymphocytes show no reactivatable virus using a total of 24 million resting CD4 T cells. CCR5-tropic, but not CXCR4-tropic, viruses were identified in HIV-1 DNA from CD4 T cells of the patient before the transplant. CD4 T cells isolated from peripheral blood after transplantation did not express CCR5 and were susceptible only to CXCR4-tropic virus ex vivo. HIV-1 Gag-specific CD4 and CD8 T cell responses were lost after transplantation, whereas cytomegalovirus-specific responses were detectable. Similarly, HIV-1-specific antibodies and avidities fell to levels comparable to those in the Berlin patient following transplantation. Although at 18 months after the interruption of treatment it is premature to conclude that this patient has been cured, these data suggest that a single allogeneic HSCT with homozygous CCR5Δ32 donor cells may be sufficient to achieve HIV-1 remission with reduced intensity conditioning and no irradiation, and the findings provide further support for the development of HIV-1 remission strategies based on preventing CCR5 expression. An adult infected with HIV-1 who underwent allogeneic haematopoietic stem-cell transplantation for Hodgkin’s lymphoma using cells from a CCR5Δ32/Δ32 donor achieved full remission of HIV-1 for 18 months after transplantation and 16 months after cessation of antiretroviral therapy.