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Nef dimerization defect abrogates HIV viremia and associated immune dysregulation in the Bone Marrow-Liver-Thymus-Spleen (BLTS) humanized mouse model.

ABSTRACT: Loss of function mutations in the human immunodeficiency virus (HIV)-negative factor (Nef) gene are associated with reduced viremia, robust T cell immune response, and delayed acquired immunodeficiency syndrome (AIDS) progression in humans. Additionally, in vitro studies have shown that mutations in Nef's dimerization interface may play a significant role in modulating viral replication and impairing host defense. However, in vivo, mechanistic studies on the role of Nef dimerization in HIV infection are lacking. Humanized rodent models with human immune cells are robust platforms for investigating the interactions between HIV and the human immune system. We recently developed the bone marrow-liver-thymus-spleen (BLTS) humanized mouse model, which carries human immune cells, as well as primary and secondary lymphoid tissues that facilitate anti-viral immune responses. Here, we employed the BLTS-humanized mouse model to demonstrate that preventing Nef dimerization abrogates HIV viremia and the associated induction of immune dysregulation (immune activation and exhaustion). This suggests that Nef dimerization may be a therapeutic target for future HIV cure strategies, which can be explored in humanized mouse models.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE165387 | GEO | 2021/03/10

REPOSITORIES: GEO

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Nef dimerization defect abrogates HIV viremia and associated immune dysregulation in the Bone Marrow-Liver-Thymus-Spleen (BLTS) humanized mouse model.

Project description:Nef dimerization defect abrogates HIV viremia and associated immune dysregulation in the Bone Marrow-Liver-Thymus-Spleen (BLTS) humanized mouse model.

| PRJNA694303 | ENA

Multi-omics analyses reveal that HIV-1 alters CD4 T cell immunometabolism to fuel virus replication

Project description:Human Immunodeficiency Virus type-1 (HIV-1)-infected individuals show metabolic alterations of CD4 T cells through unclear mechanisms with undefined consequences. We analyzed the transcriptome of CD4 T cells from HIV-1 patients and revealed that elevated oxidative phosphorylation (OXPHOS) pathway is associated with poor outcomes. Inhibition of OXPHOS by the FDA-approved drug metformin, which targets mitochondrial respiratory chain complex I, suppresses HIV-1 replication in human CD4 T cells and humanized mice. In patients, HIV-1 peak viremia positively correlates with the expression of NLRX1, a mitochondrial innate immune receptor. Quantitative proteomics and metabolic analyses reveal that NLRX1 enhances OXPHOS and glycolysis during HIV-1-infection of CD4 T cells to promote viral replication. At the mechanistic level, HIV infection induces the association of NLRX1 with the mitochondrial protein, FASTKD5, to promote the expression of mitochondrial respiratory complex components. This study uncovers the OXPHOS pathway in CD4 T cells as a target for HIV-1 therapy.

2022-02-16 | PXD023565 | Pride

Transcription profiling of human CD14+ peripheral blood monocytes from HIV patients vs uninfected controls suggest that monocyte function is diminished during high-level HIV viremia and that this effect is mediated by chronic stimulation by type I interferons

Project description:The effect of human immunodeficiency virus (HIV) infection and high-level HIV replication on the function of monocytes was investigated. HIV-positive patients had elevated levels of spontaneous production of some or all of the monocyte proinflammatory cytokines measured (interleukin-1beta [IL-1beta], IL-6, and tumor necrosis factor alpha [TNF-alpha]) compared to uninfected controls. In patients on therapy with high frequencies of monocytes producing proinflammatory cytokines, this frequency was diminished in the context of viremia during an interruption of therapy. Diminished production of proinflammatory cytokines during viremia was restored by culture with autologous CD4(+) T cells or monocytes from an on-therapy time point or lipopolysaccharide (LPS). Microarray analysis demonstrated that diminished monocyte production of proinflammatory cytokines was correlated with elevated type I interferon-stimulated gene transcripts. The addition of exogenous alpha 2A interferon diminished the spontaneous production of IL-1beta, IL-6, and TNF-alpha but did not affect responses to LPS, recapitulating the changes observed for HIV-viremic patients. These results suggest that monocyte function is diminished during high-level HIV viremia and that this effect is mediated by chronic stimulation by type I interferons. This effect on monocytes during viremia may play a role in diminished innate or adaptive immune system functions in HIV-infected patients. In addition, the restoration of these functions may also play a role in some immune reconstitution syndromes observed during initiation of therapy.

2007-10-26 | E-GEOD-5220 | biostudies-arrayexpress

Gene expression in the blood of Live Attenuated Rev-Independent Nef¯SIV infected Rhesus macaques during acute infection

Project description:Rhesus macaques (RMs) inoculated with live-attenuated Rev-Independent Nef¯ simian immunodeficiency virus (Rev-Ind Nef¯SIV) as adults or neonates controlled viremia to undetectable levels and showed no signs of immunodeficiency over 6-8 years of follow-up. We tested the capacity of this live-attenuated virus to protect RMs against pathogenic, heterologous SIVsmE660 challenges

2013-08-09 | GSE49663 | GEO

HIV-1 Nef changes the proteome of T cells extracellular vesicles

Project description:Extracellular vesicles (EVs) are biomolecule carriers for intercellular communication in health and disease. Nef is a human immunodeficiency virus (HIV) virulence factor that is released from cells within EVs and is present in plasma EVs of HIV-1 infected individuals. We performed a quantitative proteomic analysis to fully characterize the Nef-induced changes in protein composition of T cell-derived EVs and identify novel host targets of HIV. Several proteins with well-described roles in infection or not previously associated with HIV pathogenesis were specifically modulated by Nef in EVs. Among the downregulated proteins are the interferon-induced transmembrane 1, 2 and 3 proteins (IFITM1-3), broad-spectrum antiviral factors known to be cell-to-cell transferable by EVs. Our data establish Nef as a modulator of EVs' global protein content and as an HIV factor that antagonizes IFITMs.

2024-01-26 | PXD041028 | Pride

Sustained viremia suppression by SHIVsf162p3cn-recalled effector-memory CD8+ T cells after PD1-based vaccination

Project description:HIV-1 functional cure requires sustained viral suppression without antiretroviral therapy. While effector-memory CD8+ T lymphocytes are essential for viremia control, few vaccines elicit such cellular immunity that could be potently recalled upon viral infection. Here, we investigated a program death-1 (PD1)-based vaccine by fusion of simian immunodeficiency virus capsid antigen to soluble PD1. Homologous vaccinations suppressed setpoint viremia to undetectable levels in all vaccinated macaques following high-dose intravenous challenge by the pathogenic SHIVSF162P3CN. Poly-functional effector-memory CD8+ T cells were not only induced after vaccination, but were also recalled upon viral challenge for viremia control as determined by CD8 depletion. Vaccine-induced effector memory CD8+ subsets displayed high cytotoxicity-related genes by single-cell analysis. Vaccinees with sustained viremia suppression for over two years responded to boost vaccination without viral rebound. These results demonstrated that PD1-based vaccine-induced effector-memory CD8+ T cells were recalled by AIDS virus infection, providing a potential immunotherapy for functional cure.

2021-05-24 | GSE171783 | GEO

Molecular signatures of mucosal immunity that distinguish HIV controllers from non-controllers

Project description:HIV â??controllersâ?? are individuals infected with the human immunodeficiency virus, type I (HIV) who maintain long-term control of viremia without antiviral therapy and who usually do not develop the acquired immune deficiency syndrome (AIDS). In this study, we have used oligonucleotide expression arrays to characterize the mucosal immune responses of these subjects in relation to untreated HIV+ individuals with high viral loads and progressive disease (â??non-controllersâ??). Recto-sigmoid biopsies were analyzed from 9 controllers and 11 non-controllers. All of the genes identified to be significantly different were more highly expressed in the non-controllers. Many of these genes are involved in immunity and defence. These results underscore the importance of the sustained inflammatory response that attends progressive HIV disease. Keywords: Recto-sigmoid biopsy profiles from HIV infected individuals We analyzed a series of 20 HEEBO arrays on which were hybed RNA amplified from the recto-sigmoid biopsies of HIV infected individuals that either have progressive disease or can maintain long term control of viremia.

2010-10-08 | E-GEOD-20075 | biostudies-arrayexpress

Integrative transcriptomic and proteomic analyses reveal that NLRX1 and FASTDK5 orchestrate immunometabolic fitness to fuel HIV-1 replication

Project description:We analyzed the transcriptome of CD4 T cells from HIV-1 patients and revealed that elevated oxidative phosphorylation (OXPHOS) pathway is associated with poor outcomes. Inhibition of OXPHOS by the FDA-approved drug metformin, which targets mitochondrial respiratory chain complex I, suppresses HIV-1 replication in human CD4 T cells and humanized mice. In patients, HIV-1 peak viremia positively correlates with the expression of NLRX1, a mitochondrial innate immune receptor.

2021-01-31 | GSE165841 | GEO

Molecular signatures of mucosal immunity that distinguish HIV controllers from non-controllers

Project description:HIV “controllers” are individuals infected with the human immunodeficiency virus, type I (HIV) who maintain long-term control of viremia without antiviral therapy and who usually do not develop the acquired immune deficiency syndrome (AIDS). In this study, we have used oligonucleotide expression arrays to characterize the mucosal immune responses of these subjects in relation to untreated HIV+ individuals with high viral loads and progressive disease (“non-controllers”). Recto-sigmoid biopsies were analyzed from 9 controllers and 11 non-controllers. All of the genes identified to be significantly different were more highly expressed in the non-controllers. Many of these genes are involved in immunity and defence. These results underscore the importance of the sustained inflammatory response that attends progressive HIV disease. Keywords: Recto-sigmoid biopsy profiles from HIV infected individuals

2010-02-02 | GSE20075 | GEO

Functional impairment of HIV-specific CD8+ T cells precedes aborted control of viremia

Project description:Spontaneous control of HIV infection has been repeatedly linked to antiviral CD8+ T cells but is not always permanent. To address mechanisms of durable and aborted control of viremia, we evaluated immunologic and virologic parameters in longitudinal samples from 34 subjects with differential outcomes. Despite sustained recognition of autologous virus, aborted control was preceded by impairment of HIV-specific proliferative and cytolytic T cell effector functions without evidence of canonical T cell exhaustion. During aborted control, HIV-specific CD8+ T cells infiltrated lymphoid follicles but exhibited poor functionality relative to durable control. Longitudinal transcriptomic profiling of HIV-specific CD8+ T cells revealed altered expression of genes related to T cell activation, cytokine-mediated signaling and cell cycle regulation preceding aborted control, including increased expression of the antiproliferative transcription factor KLF2. Our results identify prognostic indicators of aborted HIV control and elucidate functional requirements for durable immune control, which may guide development of new therapies

2021-08-30 | GSE168296 | GEO

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