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HIV-1 integrase variants retarget viral integration and are associated with disease progression in a chronic infection cohort.

ABSTRACT: Distinct integration patterns of different retroviruses have puzzled virologists for over 20 years. The viral integrase (IN), as part of the intasome complex, docks onto the target DNA (tDNA) and catalyzes the insertion of the viral genome into the host chromatin. We identified retroviral IN amino acids directly contacting tDNA bases and affecting the local integration site sequence biases. These residues also determine the propensity of the virus to integrate into flexible tDNA sequences. Remarkably, natural polymorphisms INS119G and INR231G retarget viral integration away from gene dense regions, without affecting the interaction with the lentiviral tethering cofactor LEDGF/p75 (PSIP1). Precisely these variants were associated with rapid disease progression in a chronic HIV-1 subtype C infection cohort. These findings link integration site selection to virulence and viral evolution but also to the host immune response and antiretroviral therapy, since HIV-1 IN119 is under selection by HLA alleles and integrase inhibitors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE61003 | GEO | 2015/01/26

SECONDARY ACCESSION(S): PRJNA260064

REPOSITORIES: GEO

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HIV-1 integrase variants retarget viral integration and are associated with disease progression in a chronic infection cohort.

Project description:Distinct integration patterns of different retroviruses have puzzled virologists for over 20 years. The viral integrase (IN), as part of the intasome complex, docks onto the target DNA (tDNA) and catalyzes the insertion of the viral genome into the host chromatin. We identified retroviral IN amino acids directly contacting tDNA bases and affecting the local integration site sequence biases. These residues also determine the propensity of the virus to integrate into flexible tDNA sequences. Remarkably, natural polymorphisms INS119G and INR231G retarget viral integration away from gene dense regions, without affecting the interaction with the lentiviral tethering cofactor LEDGF/p75 (PSIP1). Precisely these variants were associated with rapid disease progression in a chronic HIV-1 subtype C infection cohort. These findings link integration site selection to virulence and viral evolution but also to the host immune response and antiretroviral therapy, since HIV-1 IN119 is under selection by HLA alleles and integrase inhibitors. LEDGF/p75 (PSIP1) ChIP-Seq using A300-848 antibody (recognizes p75 isoform) and input control in primary CD4+ T-cells

2015-01-26 | E-GEOD-61003 | biostudies-arrayexpress

CLIP-seq analysis of integrase-RNA interactions

2016-08-25 | GSE83588 | GEO

CLIP-seq analysis of integrase-RNA interactions

Project description:Integrase CLIP-seq experiments were conducted on wild-type and eccentric HIV-1 virions generated in the presence of allosteric integrase inhibitors and IN K264/266A and R269/K273A mutations Integrase CLIP-seq experiments were conducted by immunoprecipitation of integrase-RNA complexes from fully formed mature and eccentric virus particles. Libraries of RNA molecules bound by integrase were generated and sequenced by Illumina Hi-Seq2000 and 2500 platforms.

2016-08-25 | E-GEOD-83588 | biostudies-arrayexpress

Molecular Signatures of retrotransposon Ty3 insertion into the RNA Polymerase III transcription initiation site (Integrase)

Project description:The Gypsy-like element Ty3 inserts proximal to the transcription start sites of genes transcribed by RNA polymerase 3 (RNAP3). In this study, a random-barcode Ty3 was used to count Ty3 insertions at specific sites. Surprisingly, saturation transposition of the yeast genome showed that tDNAs even within isoacceptor families are targeted at widely different frequencies. Ectopic expression of Ty3 integrase showed that it localizes to integration targets independent of other Ty3 proteins. Binding of integrase, RNAP3 and factor Brf1 at individual targets did not differ to the same extent as integration. Metadata analysis showed that histone modification H3K4Ac correlated positively with insertion frequency. Targeting frequency could be reconstituted on high copy plasmids containing only 75 bp of 5’ flanking sequence plus the tDNA target. Weighting of insertions according to frequency identified an A/T-rich sequence followed by C as the site of gene-proximal strand transfer. This site lies immediately adjacent to the adenines of the RNAP3 transcription start site motif (CAA). Recent structures of DNA in RNAP3 initiation complexes show that in the initiation complex the transcription start site is sharply bent at the position adjacent to the gene-proximal Ty3 strand transfer. We propose that Ty3 integration occurs in two steps: in the first, host Brf1 engages integrase; in the second, integrase exploits YR flexibility, and that together, these steps determine the wide range of Ty3 targeting frequencies.

2018-04-15 | GSE97892 | GEO

The chromatin landscape at the HIV-1 provirus integration site determines viral expression

Project description:We investigated the link between HIV-1 integration by using B-HIVE and LEDGINs. B-HIVE tracks insert-specific HIV expression by tagging a unique barcode in the HIV genome. LEDGINs are antivirals that inhibit the interaction between HIV-IN and its chromatin tethering cofactor LEDGF/p75. They are known to retarget HIV-1 integration sites. Here, we confirmed that LEDGIN treatment retargets integration out of transcriptionally active regions and reduce HIV expression. Silent provirus was located at increased distance to H3K36me3, the recognition marker of LEDGF/p75, after treatment with LEDGINs. Viral RNA expression was also influenced by the proximity of enhancers, regardless of the presence of LEDGINs.

2020-07-03 | GSE135295 | GEO

CTNNBL1 restricts HIV-1 replication

Project description:Retroviral integration is mediated by a unique enzymatic process shared by all retroviruses and retrotransposons. During integration, double-stranded linear viral DNA is inserted into the host genome in a process catalyzed by viral-encoded integrase. However, host cell defenses against HIV-1 integration are not clear. This study identifies -catenin-like protein 1 (CTNNBL1) as a potent inhibitor of HIV-1 integration via association with viral IN and its cofactor, lens epithelium-derived growth factor/p75. CTNNBL1 overexpression blocks HIV-1 integration and inhibits viral replication, whereas CTNNBL1 depletion significantly upregulates HIV-1 integration into the genome of various target cells. Further, CTNNBL1 expression is downregulated in CD4+ T cells by activation, and CTNNBL1 depletion also facilitates HIV-1 integration in resting CD4+ T cells. Thus, host cells may employ CTNNBL1 to inhibit HIV-1 integration into the genome. This finding suggests a strategy for the treatment of HIV infections.

2022-02-24 | PXD031853 | iProX

Homo sapiens

Project description:HIV-1 integrase variants retarget viral integration and are associated with disease progression in a chronic infection cohort.

| PRJNA260064 | ENA

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Project description:Adult T-cell Leukemia (ATL) is a highly chemoresistant malignancy of peripheral T lymphocytes, associated with retrovirus human T-cell leukemia virus type I (HTLV-1). To elucidate the complex molecular mechanism of anti-Growth effect of the HIV integrase inhibitor, MK-2048 in ATL cells, we attempted to perform gene expression profiling.

2020-01-01 | GSE113265 | GEO

Transcription profiling of human cord lining epithelial cells after phage integrase mediated integration

Project description:The two obstacles that impede a wider application of genetically modified cells expressing therapeutic transgenes for ex vivo gene therapy are the immune mediated rejection of the transplanted cells, combined with their potential to cause iatrogenic oncogenesis. In this study we describe a new cellular vehicle for this form of therapy,; termed the cord lining epithelial cell (CLEC). CLECs are derived from the human amnion and incorporate many of the immunoregulatory functions associated with the fetal/maternal interface. We show that CLECs can be safely transfected by phage ÏC31 integrase to accomplish site-specific integration of a therapeutic human transgene. We also show that transplanted CLECs are not oncogenic in vivo and can be maintained in immunocompetent mice where acute xeno-rejection rapidly destroys other human cell types. Finally, we demonstrate the utility of CLECs for ex vivo gene therapy by delivering human coagulation factor 8 to mice with Hemophilia A. Experiment Overall Design: The transcriptome datasets of human umbilical cord lining epithelial cells were compared before(CLEC) and 1 month after(CLEC-GFP) phage integrase mediated integration of EGFP cDNA into the genome. Transcriptome datasets were generated in singles and genes differentiallty expressed in cells before and after phage integrase treatment were analysed. Genes differentially expressed by at least 2 fold as compared to untreated CLEC were considered to be significantly dysregulated. List of genes with significant dysregulation were used for further analysis and to used to determine if genomic integration events had resulted in any potential geno-toxicity.

2008-10-25 | E-GEOD-12510 | biostudies-arrayexpress

HIV integrase deep sequencing.

Project description:Identification of minority resistance mutations in the HIV-1 integrase gene using Next Generation Sequencing

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