HSF1 Activation Can Restrict HIV Replication
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA565977 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10133010.fastq.gz | Fastqsanger.gz | |||
| SRR10133011.fastq.gz | Fastqsanger.gz | |||
| SRR10133012.fastq.gz | Fastqsanger.gz | |||
| SRR10133013.fastq.gz | Fastqsanger.gz | |||
| SRR10133014.fastq.gz | Fastqsanger.gz |
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Project description:Host protein folding stress responses can play important roles in RNA virus replication and evolution. Intriguingly, prior work revealed a complicated interplay between the cytosolic proteostasis stress response, controlled by its master regulator heat shock factor 1 (HSF1) and human immunodeficiency virus-1 (HIV-1). We sought to isolate HSF1 transcription factor activity from proteostasis stress and elucidate the function of HSF1 in HIV-1 lifecycle in absence of cellular stress. We used chemical genetic, stress-independent control of HSF1 activity to establish whether and how HSF1 influences HIV-1 replication. Stress-independent HSF1 induction decreased both the total quantity and infectivity of HIV-1 virions. Moreover, HIV-1 was unable to escape HSF1-mediated restriction over the course of several serial passages. These results promote continued consideration of the heat shock response as a potential target for antiviral drugs.
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Project description:Host protein folding stress responses can play important roles in RNA virus replication and evolution. Prior work suggested a complicated interplay between the cytosolic proteostasis stress response, controlled by the transcriptional master regulator heat shock factor 1 (HSF1), and human immunodeficiency virus-1 (HIV-1). We sought to uncouple HSF1 transcription factor activity from cytotoxic proteostasis stress and thereby better elucidate the proposed role(s) of HSF1 in the HIV-1 lifecycle. To achieve this objective, we used chemical genetic, stress-independent control of HSF1 activity to establish whether and how HSF1 influences HIV-1 replication. Stress-independent HSF1 induction decreased both the total quantity and infectivity of HIV-1 virions. Moreover, HIV-1 was unable to escape HSF1-mediated restriction over the course of several serial passages. These results clarify the interplay between the host's heat shock response and HIV-1 infection and motivate continued investigation of chaperones as potential antiviral therapeutic targets.
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Project description: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.
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Project description:Stress responses are a key feature of normal physiology and are usurped by cancer cells to ensure enhanced protein synthesis for growth, to compensate for genomic instability, and to protect cancer cells from therapy induced stress. Heat shock factor-1 (HSF1) is a major stress-response transcription factor, and its activity is markedly enhanced in cancer. Stress induces HSF1 conformational changes and post-translational modifications, leading to assembly of active HSF1 trimers that bind DNA to control target gene expression. Although the function of HSF1 in transcription is relatively well-known, the mechanisms leading to HSF1 activation and enhanced stress response in tumours are unclear. To investigate whether HSF1 is a primary sensor of proteotoxic stress in vivo, we studied the range of conditions that can cause HSF1 activation in vitro and in cells, and conditions that prevent its activation. We show that purified recombinant HSF1 adopts a stable monomeric conformation in vitro. Heat stress caused a conformational change and the assembly of HSF1 trimers. Conditions leading to protein denaturation, including heat stress, crowding, Hsp90 inhibition, or proteasome inhibition, all directly lead to HSF1 activation. In contrast, HSF1 activation in vivo is prevented by proteosynthesis inhibition, which reduces the amount of denatured proteins in the cell. These results establish that HSF1 is a direct sensor of proteotoxic stress, independent of post-translational modification, where abrupt environmental changes that cause protein denaturation simultaneously induce a conformational change in monomeric HSF1 leading to its activation. This mechanism explains the universal ability of cells to respond to proteotoxic stress and trigger a protective response when increased chaperone activities are required to restore homeostasis.
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Project description:Cell activation is a vital step for T cell memory/effector differentiation as well as for productive HIV infection. To identify novel regulators of this process, we used next generation sequencing to profile changes in microRNA expression occurring in purified human naive CD4 T cells in response to TCR stimulation and HIV infection. HIV infection had no significant impact on global miR expression in quiescent nave CD4 T cells. We identified miR-34c-5p as a novel miR strongly induced by TCR stimulation of nave CD4 T cells, and found that it was consistently down-regulated in response to viral infection. Over-expression of miR-34c-5p had a positive effect on HIV-1 replication. Finally, we demonstrated that miR-34c-5p alters the expression of several genes involved in TCR signaling and cell activation, identifying it as a novel regulator of nave CD4 T cell activation potentially targeted by HIV infection.
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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.
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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
Project description:During HIV-1 infection, there is a massive perturbation of host gene expression, but as yet, genome-wide studies have not identified host genes affecting HIV-1 replication in lymphatic tissue, the primary site of virus-host interactions. In this study, we isolated RNA from the inguinal lymph nodes of 22 HIV-1-infected individuals and utilized a microarray approach to identify host genes critically important for viral replication in lymphatic tissue by examining gene expression associated with viral load. Strikingly, ~95% of the transcripts (558) in this data set (592 transcripts total) were negatively associated with HIV-1 replication. Genes in this subset (1) inhibit cellular activation/proliferation (ex.: TCFL5, SOCS5 and SCOS7, KLF10), (2) promote heterochromatin formation (ex.: HIC2, CREBZF, ZNF148/ZBP-89), (3) increase collagen synthesis (ex.: PLOD2, POSTN, CRTAP), and (4) reduce cellular transcription and translation. Potential anti-HIV-1 restriction factors were also identified (ex.: NR3C1, HNRNPU, PACT). Only ~5% of the transcripts (34) were positively associated with HIV-1 replication. Paradoxically, nearly all these genes function in innate and adaptive immunity, particularly highlighting a heightened interferon system. The predominance of negative correlations as well as the disconnect between host defenses and viral load point to the importance of genes that regulate target cell activation and genes that code for potentially new restriction factors as determinants of viral load rather than conventional host defenses. Total RNA was isolated from the inguinal lymph nodes of 22 HIV-1-infected subjects at different clinical stages (and varying viral loads) and prepared for RNA extraction and hybridization on Affymetrix Human Genome U133 Plus 2.0 microarrays. Replicate arrays were performed for lymph node samples to minimize assay noise and host genes critically important for viral replication in lymphatic tissue were identified by examining gene expression and its association with viral load. Replicates were not performed for samples WB91 and TS35 due to limited amounts of biomaterial.
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