Aminobisphosphonates reactivate the latent reservoir in people living with HIV-1
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA931626 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy 1. Current research efforts to cure HIV-1 infection include “shock and kill” strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells 2. However, the modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy 3,4. Aminobisphosphonates that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies 5. Here, we show the use of aminobisphosphonates as a novel class of LRA: we found in ex vivo assays using primary cells from ART-suppressed people living with HIV-1 that aminobisphosphonates induce HIV-1 from latency to levels that are comparable to the T cell activator phytohemagglutinin. RNA sequencing and mechanistic data suggested that reactivation may occur through activation of the activator protein 1 signaling pathway. Stored samples from a prior clinical trial aimed at analyzing the effect of alendronate on bone mineral density, provided further of alendronate-mediated latency reversal and activation of immune effector cells.Decay of the reservoir measured by IPDA was however not detected. Our results demonstrate the novel use of aminobisphosphonates to reverse HIV-1 latency while inducing immune effector functions. This preliminary evidence merits further investigation in a controlled clinical setting possibly in combination with therapeutic vaccination.
2023-09-13 | GSE224546 | GEO
Project description:Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy. Current research efforts to cure HIV-1 infection include "shock and kill" strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells. The modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy. Aminobisphosphonates (N-BPs) that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies. Here, we show the use of N-BPs as a novel class of LRA: we found in ex vivo assays using primary cells from ART-suppressed people living with HIV-1 that N-BPs induce HIV-1 from latency to levels that are comparable to the T cell activator phytohemagglutinin (PHA). RNA sequencing and mechanistic data suggested that reactivation may occur through activation of the activator protein 1 signaling pathway. Stored samples from a prior clinical trial aimed at analyzing the effect of alendronate on bone mineral density, provided further evidence of alendronate-mediated latency reversal and activation of immune effector cells. Decay of the reservoir measured by IPDA was however not detected. Our results demonstrate the novel use of N-BPs to reverse HIV-1 latency while inducing immune effector functions. This preliminary evidence merits further investigation in a controlled clinical setting possibly in combination with therapeutic vaccination.
| S-EPMC10516574 | biostudies-literature
Project description:The study examined proviral and neighboring gene transcription at sites of intact latent HIV-1 integration in cultured T cells obtained directly from people living with HIV, as well as engineered primary T cells and cell lines and showed that the site of integration has a dominant effect on the transcriptional activity of intact HIV-1 proviruses in the latent reservoir
2024-06-25 | GSE267988 | GEO
Project description:The study examined proviral and neighboring gene transcription at sites of intact latent HIV-1 integration in cultured T cells obtained directly from people living with HIV, as well as engineered primary T cells and cell lines and showed that the site of integration has a dominant effect on the transcriptional activity of intact HIV-1 proviruses in the latent reservoir
2024-06-25 | GSE267987 | GEO
Project description:A growing body of data suggests that the human brain serves as a sanctuary for HIV persistence despite life-long antiretroviral therapy. Microglia, the innate immune cells of the brain parenchyma, may serve as a reservoir for rebound of HIV infection. The extent of the latent brain reservoir and molecular phenotype of HIV infected microglia cells, however, are unknown. To address this major knowledge gap, we leveraged the ‘Last Gift’ rapid autopsy cohort to perform a multi-omics approach (single cell RNA-seq, single cell ATAC-seq, and H3K27ac ChIP-seq) of the myeloid compartment creating a gene expression and chromatin accessibility atlas of human microglia isolated from three male individuals with HIV on suppressive antiretroviral therapy.
2024-02-01 | GSE221687 | GEO
Project description:A growing body of data suggests that the human brain serves as a sanctuary for HIV persistence despite life-long antiretroviral therapy. Microglia, the innate immune cells of the brain parenchyma, may serve as a reservoir for rebound of HIV infection. The extent of the latent brain reservoir and molecular phenotype of HIV infected microglia cells, however, are unknown. To address this major knowledge gap, we leveraged the ‘Last Gift’ rapid autopsy cohort to perform a multi-omics approach (single cell RNA-seq, single cell ATAC-seq, and H3K27ac ChIP-seq) of the myeloid compartment creating a gene expression and chromatin accessibility atlas of human microglia isolated from three male individuals with HIV on suppressive antiretroviral therapy.
2024-02-01 | GSE221686 | GEO
Project description:A growing body of data suggests that the human brain serves as a sanctuary for HIV persistence despite life-long antiretroviral therapy. Microglia, the innate immune cells of the brain parenchyma, may serve as a reservoir for rebound of HIV infection. The extent of the latent brain reservoir and molecular phenotype of HIV infected microglia cells, however, are unknown. To address this major knowledge gap, we leveraged the ‘Last Gift’ rapid autopsy cohort to perform a multi-omics approach (single cell RNA-seq, single cell ATAC-seq, and H3K27ac ChIP-seq) of the myeloid compartment creating a gene expression and chromatin accessibility atlas of human microglia isolated from three male individuals with HIV on suppressive antiretroviral therapy.
2024-02-01 | GSE221685 | GEO
Project description:The latent HIV reservoir in the brain of people with HIV under antiretroviral therapy
| PRJNA915374 | ENA
Project description:Benzotriazoles reactivate latent HIV-1 through inactivation of STAT5 SUMOylation
| PRJNA328275 | ENA
Project description:Despite antiretroviral therapy, HIV mainly persists in memory CD4+ T cells in people living with HIV. Most long-lived viral reservoir cells are infected near the time of therapy initiation. A better understanding of the early events in reservoir seeding presents opportunities for preventing latent reservoir formation. Here, we demonstrated that CD4+ T cells expressing CCR5, permissive to HIV-1 infection, are effector or terminally differentiated cells. BACH2 is expressed by a small subset of CCR5+ cells and reverses their terminal differentiation. BACH2-mediated memory differentiation is impeded due to heightened inflammation before treatment initiation. Mice with a BACH2 knockout human immune system has a reduced frequency of HIV-1 reservoir cells and do not experience virus rebound after treatment discontinuation. Our study reveals that BACH2 is essential to the seeding of long-lived HIV-1 reservoir and demonstrates the potential of targeting BACH2 at the time of treatment initiation to eliminate HIV-1 reservoirs in T cells.
2024-11-01 | GSE275936 | GEO