Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tat is a critical viral transactivator essential for human immunodeficiency virus (HIV) gene expression. Activation involves binding to an RNA stem-loop structure and recruitment of the positive transcription elongation factor b. Tat also induces the remodeling of a single nucleosome in the HIV promoter. However, the mechanism of this remodeling has remained unclear. Knockdown of INI-1 and BRG-1, two components of the SWI/SNF chromatin-remodeling complex, suppressed Tat-mediated transactivation. Cells lacking INI-1 (G401 and MON) or BRG-1 (C33A) exhibited defective transactivation by Tat that was restored upon INI-1 and BRG-1 expression, respectively. Tat was co-immunoprecipitated with several SWI/SNF subunits, including INI-1, BRG-1, and beta-actin. The SWI/SNF complex interacted with the integrated HIV promoter in a Tat-dependent manner. We also found that INI-1 and BRG-1 synergized with the p300 acetyltransferase to activate the HIV promoter. This synergism depended on the acetyltransferase activity of p300 and on Tat Lys(50) and Lys(51). In conclusion, Tat-mediated activation of the HIV promoter requires the SWI/SNF complex in synergy with the coactivator p300.
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PMID:The SWI/SNF chromatin-remodeling complex is a cofactor for Tat transactivation of the HIV promoter. 1668 3

To replicate, human immunodeficiency virus, type 1 (HIV-1) needs to integrate a cDNA copy of its RNA genome into a chromosome of the host cell, a step controlled by the viral integrase (IN) protein. Viral integration involves the participation of several cellular proteins. SNF5/Ini1, a subunit of the SWI/SNF chromatin remodeling complex, was the first cofactor identified to interact with IN. We report here that SNF5/Ini1 interferes with early steps of HIV-1 replication. Inhibition of SNF5/Ini1 expression by RNA interference increases HIV-1 replication. Using quantitative PCR, we show that both the 2-long terminal repeat circle and integrated DNA forms accumulate upon SNF5/Ini1 knock down. By yeast two-hybrid assay, we screened a library of HIV-1 IN random mutants obtained by PCR random mutagenesis using SNF5/Ini1 as prey. Two different mutants of interaction, IN E69G and IN K71R, were impaired for SNF5/Ini1 interaction. The E69G substitution completely abolished integrase catalytic activity, leading to a replication-defective virus. On the contrary, IN K71R retained in vitro integrase activity. K71R substitution stimulates viral replication and results in higher infectious titers. Taken together, these results suggest that, by interacting with IN, SNF5/Ini1 interferes with early steps of HIV-1 infection.
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PMID:Inhibition of early steps of HIV-1 replication by SNF5/Ini1. 1677 95

The human immunodeficiency virus type 1 (HIV-1) Tat is a 14-kDa viral protein that acts as a potent transactivator by binding to the transactivation-responsive region, a structured RNA element located at the 5' end of all HIV-1 transcripts. Tat transactivates viral gene expression by inducing the phosphorylation of the C-terminal domain of RNA polymerase II through several Tat-activated kinases and by recruiting chromatin-remodeling complexes and histone-modifying enzymes to the HIV-1 long terminal repeat. Histone acetyltransferases, including p300 and hGCN5, not only acetylate histones but also acetylate Tat at lysine positions 50 and 51 in the arginine-rich motif. Acetylated Tat at positions 50 and 51 interacts with a specialized protein module, the bromodomain, and recruits novel factors having this particular domain, such as P/CAF and SWI/SNF. In addition to having its effect on transcription, Tat has been shown to be involved in splicing. In this study, we demonstrate that Tat interacts with cyclin-dependent kinase 13 (CDK13) both in vivo and in vitro. We also found that CDK13 increases HIV-1 mRNA splicing and favors the production of the doubly spliced protein Nef. In addition, we demonstrate that CDK13 acts as a possible restriction factor, in that its overexpression decreases the production of the viral proteins Gag and Env and subsequently suppresses virus production. Using small interfering RNA against CDK13, we show that silencing of CDK13 leads to a significant increase in virus production. Finally, we demonstrate that CDK13 mediates its effect on splicing through the phosphorylation of ASF/SF2.
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PMID:CDK13, a new potential human immunodeficiency virus type 1 inhibitory factor regulating viral mRNA splicing. 1848 Apr 52

Neuronal loss, reactive astrocytes, and other abnormalities are seen in the brain of individuals with acquired immune deficiency syndrome-associated Dementia Complex (ADC). Human immunodeficiency virus-1 (HIV-1) is believed to be the main agent causing ADC. However, little is known about the molecular and cellular mechanisms of HIV-1 neurotoxicity considering that HIV-1 does not infect post-mitotic neurons and that viral load does not necessarily correlate with ADC. Various viral proteins, such as the envelope protein gp120 and the transcription activator Tat, have been shown to induce neuronal apoptosis through direct and indirect mechanisms both in vitro and in vivo. Progeny HIV-1 virions can also cause neuronal death. However, it has not been fully established yet whether HIV-1 promotes neuronal apoptosis by a direct mechanism. To explore the neurotoxic effect of HIV-1, we exposed rat cerebellar granule cells and cortical neurons in culture to two different strains of HIV-1, IIIB and BaL, T- and M-tropic strains that utilize CXCR4 and CCR5 coreceptors, respectively, to infect cells. We observed that both viruses elicit a time-dependent apoptotic cell death in these cultures without inducing a productive infection as determined by the absence of the core protein of HIV-1, p24, in cell lysates. Instead, neurons were gp120 positive, suggesting that the envelope protein is shed by the virus and then subsequently internalized by neurons. The CXCR4 receptor antagonist AMD3100 or the CCR5 receptor inhibitor D-Ala-peptide T-amide blocked HIV IIIB and HIV Bal neurotoxicity, respectively. In contrast, the N-methyl-D-aspartate receptor blocker MK801 failed to protect neurons from HIV-mediated apoptosis, suggesting that HIV-1 neurotoxicity can be initiated by the viral protein gp120 binding to neuronal chemokine receptors.
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PMID:M- and T-tropic HIVs promote apoptosis in rat neurons. 1903 68

Integrase interactor 1 (Ini1/hSNF5/BAF47/SMARCB1), the core subunit of the ATP-dependent chromatin-remodelling complex SWI/SNF, is a cellular interaction partner of the human immunodeficiency virus type 1 (HIV-1) integrase. Ini1/hSNF5 is recruited to HIV-1 pre-integration complexes before nuclear migration, suggesting a function in the integration process itself or a contribution to the preferential selection of transcriptionally active genes as integration sites of HIV-1. More recent evidence indicates, however, that, whilst Ini1/hSNF5 is dispensable for HIV-1 transduction per se, it may have an inhibitory effect on the early steps of HIV-1 replication but facilitates proviral transcription by enhancing Tat function. These partially contradictory observations prompted an investigation of the immediate and long-term effects of Ini1/hSNF5 depletion on the basal transcriptional potential of the virus promoter. Using small interfering RNAs, it was shown that Ini1/hSNF5-containing SWI/SNF complexes mediate transcriptional repression of the basal activity of the integrated HIV-1 long terminal repeat. Transient depletion of Ini1/hSNF5 during integration was accompanied by an early boost of HIV-1 replication. After the reappearance of Ini1/hSNF5, expression levels decreased and this was associated with increased levels of histone methylation at the virus promoter in the long term, indicative of epigenetic gene silencing. These results demonstrate the opposing effects of Ini1/hSNF5-containing SWI/SNF complexes on basal and Tat-dependent transcriptional activity of the HIV-1 promoter. It is proposed that Ini1/hSNF5 may be recruited to the HIV-1 pre-integration complex to initiate, immediately after integration, one of two mutually exclusive transcription programmes, namely post-integration latency or high-level, Tat-dependent gene expression.
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PMID:Integrase interactor 1 (Ini1/hSNF5) is a repressor of basal human immunodeficiency virus type 1 promoter activity. 1951 27

To elucidate the epigenetic regulation of Tat-independent human immunodeficiency virus (HIV) transcription following proviral integration, we constructed an HIV type 1 (HIV-1)-based replication-defective viral vector that expresses a reporter green fluorescent protein (GFP) product from its intact long terminal repeat (LTR). We transduced this construct into human tumor cell lines that were either deficient in or competent for the Brm-type SWI/SNF complex. One day after transduction, single cells that expressed GFP were sorted, and the GFP expression profiles originating from each of these clones were analyzed. Unlike clones of the SWI/SNF-competent cell line, which exhibited clear unimodal expression patterns in all cases, many clones originating from Brm-deficient cell lines either showed a broad-range distribution of GFP expression or were fully silenced. The resorting of GFP-negative populations of these isolated clones showed that GFP silencing is either reversible or irreversible depending upon the proviral integration sites. We further observed that even in these silenced clones, proviral gene transcription initiates to accumulate short transcripts of around 60 bases in length, but no elongation occurs. We found that this termination is caused by tightly closed nucleosome-1 (nuc-1) at the 5' LTR. Also, nuc-1 is remodeled by exogenous Brm in some integrants. From these results, we propose that Brm is required for the occasional transcriptional elongation of the HIV-1 provirus in the absence of Tat. Since the Brm-type SWI/SNF complex is expressed at marginal levels in resting CD4+ T cells and is drastically induced upon CD4+ T-cell activation, we speculate that it plays crucial roles in the early Tat-independent phase of HIV transcription in affected patients.
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PMID:Loss of the Brm-type SWI/SNF chromatin remodeling complex is a strong barrier to the Tat-independent transcriptional elongation of human immunodeficiency virus type 1 transcripts. 1972 4

SMARCAL1 (also known as HARP) is a SWI/SNF family protein with an ATPase activity stimulated by DNA containing both single-stranded and double-stranded regions. Mutations in SMARCAL1 are associated with the disease Schimke immuno-osseous dysplasia, a multisystem autosomal recessive disorder characterized by T cell immunodeficiency, growth inhibition, and renal dysfunction. The cellular function of SMARCAL1, however, is unknown. Here, using Xenopus egg extracts and mass spectrometry, we identify SMARCAL1 as a protein recruited to double-stranded DNA breaks. SMARCAL1 binds to double-stranded breaks and stalled replication forks in both egg extract and human cells, specifically colocalizing with the single-stranded DNA binding factor RPA. In addition, SMARCAL1 interacts physically with RPA independently of DNA. SMARCAL1 is phosphorylated in a caffeine-sensitive manner in response to double-stranded breaks and stalled replication forks. It has been suggested that stalled forks can be stabilized by a mechanism involving caffeine-sensitive kinases, or they collapse and subsequently recruit Rad51 to promote homologous recombination repair. We show that depletion of SMARCAL1 from U2OS cells leads to increased frequency of RAD51 foci upon generation of stalled replication forks, indicating that fork breakdown is more prevalent in the absence of SMARCAL1. We propose that SMARCAL1 is a novel DNA damage-binding protein involved in replication fork stabilization.
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PMID:Identification of SMARCAL1 as a component of the DNA damage response. 1984 79

The human immunodeficiency virus type 1 (HIV-1) long terminal repeat is present on both ends of the integrated viral genome and contains regulatory elements needed for transcriptional initiation and elongation. Post-integration, a highly ordered chromatin structure consisting of at least five nucleosomes, is found at the 5' long terminal repeat, the location and modification state of which control the state of active viral replication as well as silencing of the latent HIV-1 provirus. In this context, the chromatin remodeling field rapidly emerges as having a critical role in the control of viral gene expression. In the current study, we focused on unique Baf subunits that are common to the most highly recognized of chromatin remodeling proteins, the SWI/SNF (switching-defective-sucrose non-fermenting) complexes. We find that at least two Baf proteins, Baf53 and Baf170, are highly regulated in HIV-1-infected cells. Previously, studies have shown that the depletion of Baf53 in uninfected cells leads to the expansion of chromosomal territories and the decompaction of the chromatin. Baf53, in the presence of HIV-1 infection, co-elutes off of a chromatographic column as a different-sized complex when compared to uninfected cells and appears to be predominantly phosphorylated. The innate function of Baf53-containing complexes appears to be transcriptionally suppressive, in that knocking down Baf53 increases viral gene expression from cells both transiently and chronically infected with HIV-1. Additionally, cdk9/cyclin T in the presence of Tat is able to phosphorylate Baf53 in vitro, implying that this posttranslationally modified form relieves the suppressive effect and allows for viral transcription to proceed.
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PMID:Varying modulation of HIV-1 LTR activity by Baf complexes. 2169 4

The human immunodeficiency virus type 1 (HIV-1) nucleocapsid (NC) is a multifunctional, zinc finger-containing protein known to be involved in almost every step of the viral life cycle. We therefore examined the effects of NC in vivo as a transcription activator on the basal transcriptional activity of the HIV-1 U3 and Rous sarcoma virus (RSV) promoters, as well as HIV-1 long terminal repeats (LTRs) such as the U3R and U3RU5 regions, using promoter-fused reporter gene assays, Western blot analyses, and quantitative real time-polymerase chain reaction. From these studies, we found that the basal transcriptional levels of the HIV-1 U3 and RSV promoters were barely enhanced by the presence of NC. Placing the U3R region upstream of reporter genes greatly increased transcriptional activity compared to that of the U3 promoter alone, and such activity was further increased by Tat expression. However, neither transcription driven by U3R itself nor Tat-mediated transcriptional activation of the U3R was further increased by the addition of NC. Similar results were also observed with U3RU5 of the HIV-1 LTR region in the presence of either NC or Gag protein. Thus, these results indicate that the HIV NC protein is unable to act as a transcriptional activator on its cognate and possibly other retroviral promoters.
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PMID:The HIV-1 nucleocapsid protein does not function as a transcriptional activator on its own cognate promoter. 2211 2

The array of genome editing strategies based on targeted double-stranded DNA break formation have recently been enriched through the introduction of transcription activator-like type III effector (TALE) nucleases (TALENs). To advance the testing of TALE-based approaches, it will be crucial to deliver these custom-designed proteins not only into transformed cell types but also into more relevant, chromosomally stable, primary cells. Viral vectors are among the most effective gene transfer vehicles. Here, we investigated the capacity of human immunodeficiency virus type 1- and adenovirus-based vectors to package and deliver functional TALEN genes into various human cell types. To this end, we attempted to assemble particles of these two vector classes, each encoding a monomer of a TALEN pair targeted to a bipartite sequence within the AAVS1 'safe harbor' locus. Vector DNA analyses revealed that adenoviral vectors transferred intact TALEN genes, whereas lentiviral vectors failed to do so, as shown by their heterogeneously sized proviruses in target cells. Importantly, adenoviral vector-mediated TALEN gene delivery resulted in site-specific double-stranded DNA break formation at the intended AAVS1 target site at similarly high levels in both transformed and non-transformed cells. In conclusion, we demonstrate that adenoviral, but not lentiviral, vectors constitute a valuable TALEN gene delivery platform.
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PMID:Differential integrity of TALE nuclease genes following adenoviral and lentiviral vector gene transfer into human cells. 2327 34


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