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Macrophages show unprecedented anti-HIV activity in HIV-infected iHMD-NSG mice

ABSTRACT: Very little is known about the role of macrophages as immune mediators during natural HIV infection. Humanized mice are a highly valuable in vivo model to study HIV pathogenesis. Still, the presence of murine mononuclear phagocytes in these models represents a significant limitation for the study of their human counterpart. Therefore, we generated a novel humanized mouse model for the selective depletion of human myeloid cells at a time point of our choosing. These inducible human myeloid cell depletion (iHMD) mice showed specific human myeloid cell depletion with no adverse events for the animals. We used this model to demonstrate that human mononuclear phagocytes restrict HIV replication in vivo by secreting antiviral cytokines and chemokines. These in vivo data were validated by a co-culture assay, showing soluble factors are at the basics of macrophage-mediated restriction of HIV. Transcriptomic data confirmed macrophages restrict HIV replication via upregulation of antiviral cytokines and chemokines. RNA sequencing CD4+ T-cells showed cellular activation, up-regulation of HIV restriction factors and the downregulation of DNA transcription and RNA translation in the presence of macrophages. This work describes a novel role of macrophages as effector cells acting against HIV replication and disease progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE269285 | GEO | 2024/06/20

REPOSITORIES: GEO

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SAMHD1 is a phospho-regulated Rnase that is essential for restricting HIV-1 infection through direct cleavage of HIV-1 genomic RNA

Project description:SAMHD1 restricts HIV-1 replication in dendritic and other myeloid cells. SAMHD1 has been shown to possess a dGTP-dependent dNTP triphosphatase (dNTPase) activity and is proposed to inhibit HIV-1 replication by depleting the intracellular dNTP pool. Arguing against a role for SAMHD1 dNTPase in HIV-1 restriction, the phosphorylation of SAMHD1 regulates the restriction activity toward HIV-1 without affecting its ability to decrease cellular dNTP levels. Here, we show that SAMHD1 is a phospho-regulated RNase and that the RNase function is required for HIV-1 restriction. Mutation of the SAMHD1 D137 residue in the allosteric site (SAMHD1D137N) abolishes dNTPase activity but has no effect on RNase activity. This dNTPase-defective SAMHD1D137N mutant is able to restrict HIV-1 infection to nearly the same extent as wild-type SAMHD1. SAMHD1 associates with and degrades the HIV-1 genomic RNA during the early phases of infection. SAMHD1 silencing in macrophages and CD4+ T cells from healthy donors increases HIV-1 RNA stability, thus rendering the cells permissive for HIV-1 infection. Furthermore, the phosphorylation of SAMHD1 at position T592 abolishes the RNase activity toward HIV-1 RNA, and consequently the ability of SAMHD1 to restrict HIV-1 infection, uncovering the phosphorylation of SAMHD1 T592 as a negative regulatory mechanism of RNase activity. Together, our results demonstrate that SAMHD1 is an essential RNase that prevents HIV-1 infection by directly degrading HIV-1 genomic RNA in a phosphorylation-regulated manner. The unique property of SAMHD1 that cleaves HIV-1 genomic RNA with no sequence preferences could be exploited to develop a new class of intervention for error-prone retroviruses. Ribosomal RNA-depleted total RNA profiles of mock, SAMHD1 wild type and mutants infected with HIV-1 were examined at the time of 0, 1, 3 h by Illumina Hiseq2500.

2014-06-13 | E-GEOD-58418 | biostudies-arrayexpress

HSF1 Activation Can Restrict HIV Replication

Project description:HSF1 Activation Can Restrict HIV Replication

| PRJNA565977 | ENA

Differential expression of microRNAs in productively HIV-1 infected and bystander macrophages in culture.

Project description:Macrophages are heterogeneous immune cells with distinct origins, phenotypes, functions and tissue localization. Their susceptibility to HIV-1 is subject to variations from permissiveness to resistance, owing in part to regulatory microRNAs. Here, we used RNAseq to examine the expression of >400 microRNAs in productively infected and bystander cells of HIV-1-exposed macrophage cultures. Two micro-RNAs up regulated in bystander macrophages, miR-221 and miR-222, were identified as negative regulators of CD4 expression and CD4-mediated HIV-1 entry. Both microRNAs were enhanced by TNF-α, an inhibitor of CD4 expression. MiR-221/miR-222 inhibitors recovered HIV-1 entry in TNF-α-treated macrophages by enhancing CD4 expression, and increased HIV-1 replication and spread in macrophages by countering TNF-α-enhanced miR-221/miR-222 expression in bystander cells. In line with these findings, HIV-1-resistant intestinal myeloid cells express higher levels of miR-221 than peripheral blood monocytes. Thus, miR-221/miR-222 act as effectors of the antiviral host response activated during macrophage infection that restrict HIV-1 entry.

2017-09-11 | GSE103394 | GEO

The ribonuclease activity of SAMHD1 is required for HIV-1 restriction

2014-06-13 | GSE58418 | GEO

HIV-1 and CA mutant stimulation

Project description:Wild type HIV-1 can infect macrophages to establish productive infection without triggering innate immune receptors or type 1 interferon responses that would otherwise restrict virus propagation. We found that HIV-1 capsid mutants that disrupt capsid interactions with two host factors CPSF6 and cyclophillin A do not replicate in macrophages because they do trigger interferon responses. Genome-wide transcriptional profiling was used to compare the repertoire of interferon stimulated genes induced by these capsid mutants after 24Êh with stimulation of macrophages with interferon-beta or with the RNA analogue Poly IC.

2014-02-12 | E-MTAB-1437 | biostudies-arrayexpress

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

Next Generation Sequencing Facilitates Quantitative Analysis of HIV Elite controller, HIV ART, HIV ART-naive and healthy control Transcriptomes

Project description:A small group of HIV-1-infected individuals, termed elite controllers (ECs), display control of HIV replication in the absence of antiretroviral therapy (ART). However, the mechanisms of resistance to HIV in ECs remains largely unknown. To identify host factors specific to the ECs that might be involved in controlling HIV infection, we performed RNA-seq transcriptome analysis, and a total of 44 samples were included. The monocytes from each sample were enriched, sequenced, and subjected to comparative transcriptome analysis to screen candidate genes that might affect resistance to HIV infection. we found several candidate genes with highly divergent expression that might contribute to the different outcomes of HIV infection in ECs and non-ECs. This finding will help elucidate the mechanisms by which ECs restrict HIV replication and represents a new approach for treatment of HIV.

2021-12-09 | GSE157198 | GEO

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

Project description: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.

2021-03-10 | GSE165387 | GEO

Genome-scale CRISPR screen reveals inhibitory factors as regulatory module of HIV

Project description:To identify host factors that restrict HIV replication, we conducted a CRISPR activation screen in a susceptible T cell line using a high-complexity, genome-wide sgRNA library. Our results identified host factors that conferred protection from HIV infection.

2022-06-04 | GSE185343 | GEO

Interferon ε protects primary macrophages against HIV infection

Project description:Interferon ε (IFNε) is a unique type I IFN that is not induced by pattern-recognition response elements. IFNε is constitutively expressed in mucosal tissues including the female genital mucosa. We show here that IFNε induces an antiviral state in human macrophages that blocks HIV-1 replication. In this work, we examined effects and underlying mechanisms of IFNε in HIV infection of monocyte-derived macrophages (MDMs). We found that IFNε blocked HIV replication in macrophages. It acted on early stages of the HIV life cycle including entry and reverse transcription. It did not appear to operate through known IFN-induced HIV host restriction factors. IFNε induced immune responses in primary macrophages distinct from those induced by IFNα. Importantly, we discovered a novel protective effect of IFNε in primary macrophages against HIV by surging reactive oxygen species (ROS).

2016-10-03 | GSE83716 | GEO

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