title: Direct non-productive HIV-1 infection in a T-cell line is driven by cellular activation state and NFκB.
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.
authors: Matthew S
authors: MS
authors: Dahabieh
authors: Department of Microbiology, The Global Health and Emerging Pathogens Institute; Mount Sinai School of Medicine, 1468 Madison Avenue, Annenberg building 18-50, New York, NY 10029, USA. marcel.ooms@mssm.edu.
authors: Marcel
authors: M
authors: Ooms
authors: Chanson
authors: C
authors: Brumme
authors: Jeremy
authors: J
authors: Taylor
authors: P Richard
authors: PR
authors: Harrigan
authors: Viviana
authors: V
authors: Simon
authors: Ivan
authors: I
authors: Sadowski
mesh_terms: D015497:HIV-1 / Q000276:immunology* / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D016328:NF-kappa B / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D016662:Virus Integration; D017735:Virus Latency; D014779:Virus Replication
chemical_list: D016328:NF-kappa B