A Genome-wide Short Hairpin RNA Screening of Jurkat T-cells for Human Proteins Contributing to Productive HIV-1 Replication

Yeung, Man Lung; Houzet, Laurent; Yedavalli, Venkat R. K.; Jeang, Kuan‐Teh

doi:10.1074/jbc.m109.010033

Cited by 230 publications

(270 citation statements)

References 36 publications

(53 reference statements)

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“…Thus, the chance that resistance mutations are selected in host mRNAs is negligible compared to HIV-1 target sequences. Recent screens revealed several cofactor-encoding mRNAs whose knock-down resulted in diminished HIV-1 replication [63][64][65][66][67] . However, knockdown of cellular proteins at the mRNA level might have negative effects on cell viability and anti-host shRNAs must be carefully designed.…”

Section: Resultsmentioning

confidence: 99%

Selection of RNAi-based inhibitors for anti-HIV gene therapy

Knoepfel

Centlivre²,

Liu³

et al. 2012

WJV

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In the last decade, RNA interference (RNAi) advanced to one of the most widely applied techniques in the biomedical research field and several RNAi therapeutic clinical trials have been launched. We focus on RNAibased inhibitors against the chronic infection with human immunodeficiency virus type 1 (HIV-1). A lentiviral gene therapy is proposed for HIV-infected patients that will protect and reconstitute the vital immune cell pool. The RNAi-based inhibitors that have been developed are short hairpin RNA molecules (shRNAs), of which multiple are needed to prevent viral escape. In ten distinct steps, we describe the selection process that started with 135 shRNA candidates, from the initial design criteria, via testing of the in vitro and in vivo antiviral activity and cytotoxicity to the final design of a combinatorial therapy with three shRNAs. These shRNAs satisfied all 10 selection criteria such as targeting conserved regions of the HIV-1 RNA genome, exhibiting robust inhibition of HIV-1 replication and having no impact on cell physiology. This combinatorial shRNA vector will soon move forward to the first clinical studies.

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Section: Resultsmentioning

confidence: 99%

Selection of RNAi-based inhibitors for anti-HIV gene therapy

Knoepfel

Centlivre²,

Liu³

et al. 2012

WJV

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“…First, we analyzed the targets of HIV, a member of the lentivirus family that causes AIDS. Putative human genes, identified to have an effect on HIV-1 replication from large-scale functional genomic screens (data compiled from four RNAi datasets) (21)(22)(23)(24) tend to be indispensable nodes ( Fig. 2C, RNAi; and Fig.…”

Section: Understanding Healthy To Disease State Transition Using Networkmentioning

confidence: 99%

Controllability analysis of the directed human protein interaction network identifies disease genes and drug targets

Vinayagam

Gibson

Lee

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

234

242

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The protein-protein interaction (PPI) network is crucial for cellular information processing and decision-making. With suitable inputs, PPI networks drive the cells to diverse functional outcomes such as cell proliferation or cell death. Here, we characterize the structural controllability of a large directed human PPI network comprising 6,339 proteins and 34,813 interactions. This network allows us to classify proteins as "indispensable," "neutral," or "dispensable," which correlates to increasing, no effect, or decreasing the number of driver nodes in the network upon removal of that protein. We find that 21% of the proteins in the PPI network are indispensable. Interestingly, these indispensable proteins are the primary targets of disease-causing mutations, human viruses, and drugs, suggesting that altering a network's control property is critical for the transition between healthy and disease states. Furthermore, analyzing copy number alterations data from 1,547 cancer patients reveals that 56 genes that are frequently amplified or deleted in nine different cancers are indispensable. Among the 56 genes, 46 of them have not been previously associated with cancer. This suggests that controllability analysis is very useful in identifying novel disease genes and potential drug targets.network biology | controllability | protein-protein interaction network | disease genes | drug targets

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“…Both biochemical studies and genome-wide short hairpin/siRNA screens have identified nucleoporins (Nups) as HIV-1 dependency factors that assist nuclear import of the preintegration complex (PIC; Ebina et al, 2004;Goff, 2008;König et al, 2008;Kok et al, 2009;Woodward et al, 2009;Yeung et al, 2009). Nups are also required for the nuclear export of viral factors during the late stages of HIV-1 replication (Zolotukhin and Felber, 1999;Hofmann et al, 2001;Le Rouzic et al, 2002;Kiss et al, 2003;Hutten and Kehlenbach, 2006;Hutten et al, 2009).…”

Section: Introductionmentioning

confidence: 99%