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Direct non-productive HIV-1 infection in a T-cell line is driven by cellular activation state and NFκB Dahabieh, Matthew S.; Ooms, Marcel; Brumme, Chanson J.; Taylor, Jeremy; Harrigan, Paul Richard; Simon, Viviana; Sadowski, Ivan

Abstract

Background: Molecular latency allows HIV-1 to persist in resting memory CD4+ T-cells as transcriptionally silent provirus integrated into host chromosomal DNA. Multiple transcriptional regulatory mechanisms for HIV-1 latency have been described in the context of progressive epigenetic silencing and maintenance. However, our understanding of the determinants critical for the establishment of latency in newly infected cells is limited. Results: In this study, we used a recently described, doubly fluorescent HIV-1 latency model to dissect the role of proviral integration sites and cellular activation state on direct non-productive infections at the single cell level. Proviral integration site mapping of infected Jurkat T-cells revealed that productively and non-productively infected cells are indistinguishable in terms of genomic landmarks, surrounding epigenetic landscapes, and proviral orientation relative to host genes. However, direct non-productive infections were inversely correlated with both cellular activation state and NFκB activity. Furthermore, modulating NFκB with either small molecules or by conditional overexpression of NFκB subunits was sufficient to alter the propensity of HIV-1 to directly enter a non-productive latent state in newly infected cells. Importantly, this modulatory effect was limited to a short time window post-infection. Conclusions: Taken together, our data suggest that cellular activation state and NFκB activity during the time of infection, but not the site of proviral integration, are important regulators of direct HIV-1 non-productive infections.

Item Metadata

Title
Direct non-productive HIV-1 infection in a T-cell line is driven by cellular activation state and NFκB
Creator
Dahabieh, Matthew S.; Ooms, Marcel; Brumme, Chanson J.; Taylor, Jeremy; Harrigan, Paul Richard; Simon, Viviana; Sadowski, Ivan
Publisher
BioMed Central
Date Issued
2014-02-07
Description
Background: Molecular latency allows HIV-1 to persist in resting memory CD4+ T-cells as transcriptionally silent provirus integrated into host chromosomal DNA. Multiple transcriptional regulatory mechanisms for HIV-1 latency have been described in the context of progressive epigenetic silencing and maintenance. However, our understanding of the determinants critical for the establishment of latency in newly infected cells is limited. Results: In this study, we used a recently described, doubly fluorescent HIV-1 latency model to dissect the role of proviral integration sites and cellular activation state on direct non-productive infections at the single cell level. Proviral integration site mapping of infected Jurkat T-cells revealed that productively and non-productively infected cells are indistinguishable in terms of genomic landmarks, surrounding epigenetic landscapes, and proviral orientation relative to host genes. However, direct non-productive infections were inversely correlated with both cellular activation state and NFκB activity. Furthermore, modulating NFκB with either small molecules or by conditional overexpression of NFκB subunits was sufficient to alter the propensity of HIV-1 to directly enter a non-productive latent state in newly infected cells. Importantly, this modulatory effect was limited to a short time window post-infection. Conclusions: Taken together, our data suggest that cellular activation state and NFκB activity during the time of infection, but not the site of proviral integration, are important regulators of direct HIV-1 non-productive infections.
Subject
HIV-1; Latency; LTR; CMV; Promoter; eGFP; mCherry; Double-label; Silent-infection; NFκB
Genre
Article
Type
Text
Language
eng
Date Available
2016-01-13
Provider
Vancouver : University of British Columbia Library
Rights
Attribution 4.0 International (CC BY 4.0)
DOI
10.14288/1.0223381
URI
http://hdl.handle.net/2429/56486
Affiliation
Biochemistry and Molecular Biology, Department of; Medicine, Faculty of; Non UBC
Citation
Retrovirology. 2014 Feb 07;11(1):17
Publisher DOI
10.1186/1742-4690-11-17
Peer Review Status
Reviewed
Scholarly Level
Faculty
Copyright Holder
Dahabieh et al.; licensee BioMed Central Ltd.
Rights URI
http://creativecommons.org/licenses/by/4.0/
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Attribution 4.0 International (CC BY 4.0)