Integration of Human Immunodeficiency Virus Type 1 in Untreated Infection Occurs Preferentially within Genes

Liu, Hongbing; Dow, Eugene C.; Arora, Reetakshi; Kimata, Jason T.; Bull, Lara; Arduino, Roberto C.; Rice, Andrew P.

doi:10.1128/jvi.00542-06

Cited by 35 publications

(21 citation statements)

References 22 publications

(24 reference statements)

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“…These loci, in which vector insertion is highly enriched, are of interest not only to the gene-trap community, but also to the gene therapy [19], cancer biology [20], and HIV fields [21]. Prior attempts to define hotspots have likely been confounded by ignoring effects of expression and length that we define here.…”

Section: Resultsmentioning

confidence: 99%

Modeling Insertional Mutagenesis Using Gene Length and Expression in Murine Embryonic Stem Cells

et al. 2007

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BackgroundHigh-throughput mutagenesis of the mammalian genome is a powerful means to facilitate analysis of gene function. Gene trapping in embryonic stem cells (ESCs) is the most widely used form of insertional mutagenesis in mammals. However, the rules governing its efficiency are not fully understood, and the effects of vector design on the likelihood of gene-trapping events have not been tested on a genome-wide scale.Methodology/Principal FindingsIn this study, we used public gene-trap data to model gene-trap likelihood. Using the association of gene length and gene expression with gene-trap likelihood, we constructed spline-based regression models that characterize which genes are susceptible and which genes are resistant to gene-trapping techniques. We report results for three classes of gene-trap vectors, showing that both length and expression are significant determinants of trap likelihood for all vectors. Using our models, we also quantitatively identified hotspots of gene-trap activity, which represent loci where the high likelihood of vector insertion is controlled by factors other than length and expression. These formalized statistical models describe a high proportion of the variance in the likelihood of a gene being trapped by expression-dependent vectors and a lower, but still significant, proportion of the variance for vectors that are predicted to be independent of endogenous gene expression.Conclusions/SignificanceThe findings of significant expression and length effects reported here further the understanding of the determinants of vector insertion. Results from this analysis can be applied to help identify other important determinants of this important biological phenomenon and could assist planning of large-scale mutagenesis efforts.

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Section: Resultsmentioning

confidence: 99%

Modeling Insertional Mutagenesis Using Gene Length and Expression in Murine Embryonic Stem Cells

et al. 2007

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“…However, the first analysis of HIV-1 integration sites in infected individuals found that HIV-1 proviruses integrated into transcriptionally active cellular genes in resting CD4 ϩ T cells from patients on HAART (18). The same pattern has been observed in peripheral blood mononuclear cells (PBMC) from untreated individuals (36). In these studies, integrated proviruses were detected by specific PCR strategies, but the replication competence of the proviruses was not assessed.…”

mentioning

confidence: 86%

Influence of Host Gene Transcription Level and Orientation on HIV-1 Latency in a Primary-Cell Model

Shan

Yang²,

Rabi³

et al. 2011

J Virol

102

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“…Studies have now shown that both gamma-retroviruses and lentiviruses preferentially integrate in transcriptionally active genes [24][25][26][27][28][29]. HIV-1 integration is influenced by a number of different factors including base composition [30], Alu repeats [31,32] and DNase I hypersensitive sites [33] and is directed by LEDGF/p75, a cellular binding partner of lentiviral integrases [34,35].…”

Section: Potential Adverse Effects Attribu-table To Lentiviral Vectorsmentioning

confidence: 99%

State-of-the-Art Lentiviral Vectors for Research Use: Risk Assessment and Biosafety Recommendations

Pauwels¹,

Gijsbers²,

Toelen³

et al. 2009

CGT

108

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Lentiviral vectors (LV) are competent gene transfer vehicles, as used for both research and gene therapy applications, because of their stable integration in non-dividing and dividing cells and long-term transgene expression. Along with our understanding that LV offer solutions for gene therapy, biosafety concerns have uncovered risks due to insertional mutagenesis, the generation of replication competent lentiviruses (RCL) and vector mobilization. Researchers therefore continue to devote significant efforts in designing LV with improved efficacy and biosafety features.The choice of a particular LV system for experimental studies is often driven by functional considerations, including increased productivity and/or transduction efficiency. The design of safer vectors has also directly benefited researchers allowing them to conduct experimental studies with lower risk. Currently, vectors combine improved safety features (that decrease the risk of recombination and vector mobilization) with increased transduction efficiency. Hence, risks associated with the inadvertent transduction of cells of the investigator gain greater importance in assessing the overall risk of these vectors and become an important biosafety concern.This review outlines the different strategies used to improve LV biosafety by comparing state-of-the-art and emerging LV production systems and highlighting biosafety issues that can arise during their contained use. The few existing national and international biosafety recommendations that specifically address the use of LV in research are discussed and recommendations for most common research activities using LV are proposed.

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Integration of Human Immunodeficiency Virus Type 1 in Untreated Infection Occurs Preferentially within Genes

Cited by 35 publications

References 22 publications

Modeling Insertional Mutagenesis Using Gene Length and Expression in Murine Embryonic Stem Cells

Modeling Insertional Mutagenesis Using Gene Length and Expression in Murine Embryonic Stem Cells

Influence of Host Gene Transcription Level and Orientation on HIV-1 Latency in a Primary-Cell Model

State-of-the-Art Lentiviral Vectors for Research Use: Risk Assessment and Biosafety Recommendations

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