Ontology highlight
ABSTRACT:
PROVIDER: PRJNA979002 | ENA |
REPOSITORIES: ENA
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Project description:Lymph node dendritic cells harbor inducible replication-competent HIV despite years of suppressive ART
| PRJNA803203 | ENA
Project description:The comprehensive characterization and quantification of the HIV tissue reservoirs is required to design appropriate therapeutic intervention(s) to achieve a cure. While pioneering studies demonstrated that HIV replication and spreading mainly occur in lymphoid tissues, the identification of specific cell subsets harboring replication competent virus in lymphoid tissues has long been neglected. In this context, we and others have recently shown that gut memory CD4 T cells, lymph node T follicular helper (Tfh) cells and tissue macrophages represent major HIV/SIV tissue reservoirs. Notably, Tfh cell differentiation is a multi-stage process that requires long-lasting interactions with lymph node (LN) dendritic cells (DCs) and pre-germinal center B cells in a specific cytokine/chemokine microenvironment. Lymph node DCs are endowed with an exceptional T-cell stimulatory potential and can either migrate from the periphery to the draining lymph node (migratory DCs) or locate in the LN for their entire life span (resident DCs). On the basis of these unique properties, long-term persistence of LN DCs infected with replication competent virus may represent the initial trigger of viral rebound post ART interruption and may therefore represent a major obstacle to HIV cure. We demonstrate that LN migratory DCs are infected with replication competent virus and persist despite suppressive ART. In addition, we identified the mechanisms associated with i) LN DC susceptibility to HIV infection and ii) long term persistence of HIV-infected LN DCs i.e. proliferation of infected cells in tissue sanctuaries.
2023-09-13 | GSE196066 | GEO
Project description:The development of biomarkers that can predict viral rebound following discontinuation of antiretroviral therapy (ART) in HIV-1-infected humans would be an important advance in HIV-1 cure research. In a prior study, we initiated ART in 20 rhesus macaques on days 0, 1, 2, and 3 following SIVmac251 infection prior to plasma viremia1. Following 6 months of suppressive ART, we discontinued ART and observed viral rebound in 9 of 20 animals. Here we show that transcriptomic and proteomic signatures of inflammation and immune activation in peripheral blood during ART suppression predicted viral rebound following ART discontinuation. Higher levels of proinflammatory and cellular immune activation pathways, including TNF, IL-1, IL-6, monocyte, and T cell activation signaling pathways, correlated with viral rebound following ART discontinuation. Immune modulatory IL-10 and TGF-b signaling also correlated with viral rebound. We then validated these candidate biomarkers of viral rebound in a second cohort of SIV-infected, ART-suppressed macaques. Taken together, these data suggest that persistent upregulation of inflammatory and immune activation pathways despite suppressive ART may represent a peripheral blood biomarker signature of the rebound-competent viral reservoir. The development of interventions that target the viral reservoir and modulate this signature may open new avenues in HIV-1 cure research.
2023-08-30 | GSE203603 | GEO
Project description:To investigate the biological differences between HIV-, HIV+/ART-experienced and HIV+/ART-naive diffuse large B-cell lymphoma, we performed RNA sequencing of 70 pre-treatment formalin-fixed paraffin-embedded (FFPE) whole lymph node biopsies of diffuse large B-cell lymphoma.
2024-06-01 | GSE262621 | GEO
Project description:The goal of this project is todetermine if natural killer (NK) cells could be able to control HIV replication and reduce or eliminate viral reservoirs leading to HIV cure or a functional cure. Despite thirty years of work and significant progress, HIV infection continues to be an incurable disease. Antiretroviral therapy (ART) has significantly decreased the morbidity and mortality, but lifelong treatment is merely suppressive and does not cure HIV/AIDS. This is because of the existence of a reservoir of viral DNA+ (vDNA+) in cells of the lymphoid tissues with an intact provirus that is thought capable of initiating new rounds of HIV replication (i.e. latency). In addition to this inducible reservoir data suggest ongoing low-level virus replication and persistence in lymphatic tissues of some patients that is related to suboptimal drug levels in these tissues. Strategies are needed that can address both issues. NK cells are innate immune effectors that recognize virally infected targets through a cadre of activating and inhibitory receptors but become dysfunctional in HIV infected people. Strikingly, African green monkeys (AGM) and sooty mangabeys mount a strong control of viral replication in lymph node follicles shortly after the viremia peak that lasts throughout infection. Several mechanisms have been proposed to be implicated in the strong control of viral replication in natural host’s lymph nodes, such as NK cell-mediated control. Indeed, we have recently shown that NK cells could migrate into the b cells follicles in a CXCR5 dependent manner and thus participate to the elimination of viral replication. Thus the purpose of this study is too compare at the transcriptomic level different subset of NK cell isolated from blood and peripheral lymph node of chronically infected AGM to identify a transcriptomic signature which could be linked to an efficient control of SIV replication. This results could then provide a new aproche which could be exploited to generate functional NK cells against HIV in infected patients.
2020-12-21 | GSE140600 | GEO
Project description:Kaiser2014 - Salmonella persistence after ciprofloxacin treatment
The model describes the bacterial tolerance to antibiotics. Using a mouse model for Salmonella diarrhea, the authors have found that bacterial persistence occurs in the presence of the antibiotic ciprofloxacin because Salmonella can exist in two different states. One, the fast-growing population that spreads in the host's tissues and the other, slow-growing "persister" population that hide out inside dendritic cells of the host's immune system and cannot be attacked by the antibiotics. However, this can be killed by adding agents that directly stimulate the host's immune defense.
This model is described in the article:
Cecum lymph node dendritic cells harbor slow-growing bacteria phenotypically tolerant to antibiotic treatment.
Kaiser P, Regoes RR, Dolowschiak T, Wotzka SY, Lengefeld J, Slack E, Grant AJ, Ackermann M, Hardt WD.
PLoS Biol. 2014 Feb 18;12(2):e1001793.
Abstract:
In vivo, antibiotics are often much less efficient than ex vivo and relapses can occur. The reasons for poor in vivo activity are still not completely understood. We have studied the fluoroquinolone antibiotic ciprofloxacin in an animal model for complicated Salmonellosis. High-dose ciprofloxacin treatment efficiently reduced pathogen loads in feces and most organs. However, the cecum draining lymph node (cLN), the gut tissue, and the spleen retained surviving bacteria. In cLN, approximately 10%-20% of the bacteria remained viable. These phenotypically tolerant bacteria lodged mostly within CD103⁺CX₃CR1⁻CD11c⁺ dendritic cells, remained genetically susceptible to ciprofloxacin, were sufficient to reinitiate infection after the end of the therapy, and displayed an extremely slow growth rate, as shown by mathematical analysis of infections with mixed inocula and segregative plasmid experiments. The slow growth was sufficient to explain recalcitrance to antibiotics treatment. Therefore, slow-growing antibiotic-tolerant bacteria lodged within dendritic cells can explain poor in vivo antibiotic activity and relapse. Administration of LPS or CpG, known elicitors of innate immune defense, reduced the loads of tolerant bacteria. Thus, manipulating innate immunity may augment the in vivo activity of antibiotics.
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2024-09-02 | BIOMD0000000527 | BioModels
Project description:Comparison of the gene expression in the two pancreatic lymph nodes: gastric lymph node (GLN) and pancreatico-duodenal lymph node (PDLN) in NOD mice. The analysis was done in an attempt to explain the preferential homing of bone marrow-derived dendritic cells to the GLN after intravenous injection.
2009-04-23 | GSE15753 | GEO
Project description:Unlike HIV infection, which progresses to AIDS absent suppressive anti-retroviral therapy (ART), nonpathogenic infections in natural hosts, such African green monkeys (AGMs), are characterized by a lack of gut microbial translocation and robust secondary lymphoid Natural Killer (NK) cell responses resulting in absence of chronic inflammation and limited SIV dissemination in lymph nodes (LN) B-cell-follicles, respectively. In a pathogenic infection model (i.e. ART-treated, SIVmac239-infected rhesus macaques; RMs), sequential Interleukin (IL)-21 and interferon (IFN)-alpha therapy generated terminally-differentiated blood NK cells (NKG2a/clowCD16+) with potent HLA-E-restricted activity in response to SIV-ENV peptides in contrast to control RMs, where less differentiated, IFN-gamma+ NK cells predominated. The frequency and cytolytic activity of NKG2a/clowCD16+ NK cells correlated with a reduction of replication-competent SIV in LN during ART and viral rebound delay following analytical treatment interruption. These data demonstrate that AGM-like NK cell differentiation profiles can be rescued in RMs to promote viral clearance in tissues.
2021-02-22 | GSE163441 | GEO
Project description:Unlike HIV infection, which progresses to AIDS absent suppressive anti-retroviral therapy (ART), nonpathogenic infections in natural hosts, such African green monkeys (AGMs), are characterized by a lack of gut microbial translocation and robust secondary lymphoid Natural Killer (NK) cell responses resulting in absence of chronic inflammation and limited SIV dissemination in lymph nodes (LN) B-cell-follicles, respectively. In a pathogenic infection model (i.e. ART-treated, SIVmac239-infected rhesus macaques; RMs), sequential Interleukin (IL)-21 and interferon (IFN)-alpha therapy generated terminally-differentiated blood NK cells (NKG2a/clowCD16+) with potent HLA-E-restricted activity in response to SIV-ENV peptides in contrast to control RMs, where less differentiated, IFN-gamma+ NK cells predominated. The frequency and cytolytic activity of NKG2a/clowCD16+ NK cells correlated with a reduction of replication-competent SIV in LN during ART and viral rebound delay following analytical treatment interruption. These data demonstrate that AGM-like NK cell differentiation profiles can be rescued in RMs to promote viral clearance in tissues.
2021-02-22 | GSE163442 | GEO
Project description:Unlike HIV infection, which progresses to AIDS absent suppressive anti-retroviral therapy (ART), nonpathogenic infections in natural hosts, such African green monkeys (AGMs), are characterized by a lack of gut microbial translocation and robust secondary lymphoid Natural Killer (NK) cell responses resulting in absence of chronic inflammation and limited SIV dissemination in lymph nodes (LN) B-cell-follicles, respectively. In a pathogenic infection model (i.e. ART-treated, SIVmac239-infected rhesus macaques; RMs), sequential Interleukin (IL)-21 and interferon (IFN)-alpha therapy generated terminally-differentiated blood NK cells (NKG2a/clowCD16+) with potent HLA-E-restricted activity in response to SIV-ENV peptides in contrast to control RMs, where less differentiated, IFN-gamma+ NK cells predominated. The frequency and cytolytic activity of NKG2a/clowCD16+ NK cells correlated with a reduction of replication-competent SIV in LN during ART and viral rebound delay following analytical treatment interruption. These data demonstrate that AGM-like NK cell differentiation profiles can be rescued in RMs to promote viral clearance in tissues.
2021-02-22 | GSE163440 | GEO