title: Unique characteristics of histone deacetylase inhibitors in reactivation of latent HIV-1 in Bcl-2-transduced primary resting CD4+ T cells.
abstract: OBJECTIVE
  The latent reservoir for HIV-1 in resting memory CD4+ T cells is a major barrier to eradication. In vitro models involving transformed cell lines have been used to search for small molecules that reactivate latent HIV-1. Histone deacetylase (HDAC) inhibitors can reverse HIV-1 latent infection. Most studies on HDAC inhibitors have been performed in cell line models that differ in important aspects from the resting CD4+ T cells that harbour latent HIV-1 in vivo. Therefore, we evaluated the potency and kinetics of HDAC inhibitors in a primary cell model of HIV-1 latency that involves resting CD4+ T cells.
  
  
  METHODS
  A green fluorescent protein (GFP)-expressing reporter virus NL4-3-Δ6-drGFP was used to generate latent infection in Bcl-2-transduced primary CD4+ T cells. Seventeen HDAC inhibitors were tested in this primary cell model. The effects of these HDAC inhibitors on the reactivation of latent HIV-1 were determined and compared with anti-CD3 and anti-CD28 co-stimulation.
  
  
  RESULTS
  In Bcl-2-transduced primary CD4+ T cells, short-term treatment with HDAC inhibitors resulted in very limited reactivation of latent HIV-1, while prolonged treatment greatly enhanced drug efficacy. The effects of HDAC inhibitors in reactivating latent HIV-1 correlated with their inhibitory effects on class I HDACs. Importantly, HIV-1 reactivated by HDAC inhibitors can quickly re-establish latent infection upon drug removal.
  
  
  CONCLUSIONS
  We identified unique features of HDAC inhibitor-induced reactivation of latent HIV-1 in primary CD4+ T cells. Our findings may be useful for the design of eradication trials.
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Shan
authors.forename: Sifei
authors.initials: S
authors.lastname: Xing
authors.forename: Hung-Chih
authors.initials: HC
authors.lastname: Yang
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Margolick
authors.forename: Robert F
authors.initials: RF
authors.lastname: Siliciano
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000821:virology*; D002478:Cells, Cultured; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism*; D006801:Humans; D013194:Staining and Labeling; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects*; D014779:Virus Replication
chemical_list: D056572:Histone Deacetylase Inhibitors; D049452:Green Fluorescent Proteins
keywords: cytotoxicity; latent reservoir; vorinostat