title: Novel structurally related compounds reactivate latent HIV-1 in a bcl-2-transduced primary CD4+ T cell model without inducing global T cell activation.
abstract: BACKGROUND
  The latent reservoir of HIV-1 in resting memory CD4+ T cells is a major barrier to curing HIV-1 infection. Eradication strategies involve reactivation of this latent reservoir; however, agents that reactivate latent HIV-1 through non-specific T cell activation are toxic.
  
  
  METHODS
  Using latently infected Bcl-2-transduced primary CD4+ T cells, we screened the MicroSource Spectrum library for compounds that reactivate latent HIV-1 without global T cell activation. Based on the structures of the initial hits, we assembled ∼50 derivatives from commercial sources and mostly by synthesis. The dose-response relationships of these derivatives were established in a primary cell model. Activities were confirmed with another model of latency (J-Lat). Cellular toxicity and cytokine secretion were tested using freshly isolated human CD4+ T cells.
  
  
  RESULTS
  We identified two classes of quinolines that reactivate latent HIV-1. Class I compounds are the Mannich adducts of 5-chloroquinolin-8-ol. Class II compounds are quinolin-8-yl carbamates. Most EC(50) values were in the 0.5-10 μM range. HIV-1 reactivation ranged from 25% to 70% for anti-CD3+ anti-CD28 co-stimulation. All quinolin-8-ol derivatives that reactivate latent HIV-1 follow Lipinski's Rule of Five, and most follow the stricter rule of three for leads. After 48 h of treatment, none of the analogues induced detectable cytokine secretion in primary resting CD4+ T cells.
  
  
  CONCLUSIONS
  We discovered a group of quinolin-8-ol derivatives that can induce latent HIV-1 in a primary cell model without causing global T cell activation. This work expands the number of latency-reversing agents and provides new possible scaffolds for further drug development research.
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Sifei
authors.initials: S
authors.lastname: Xing
authors.forename: Shridhar
authors.initials: S
authors.lastname: Bhat
authors.forename: Neeta S
authors.initials: NS
authors.lastname: Shroff
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Lopez
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Margolick
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
authors.forename: Robert F
authors.initials: RF
authors.lastname: Siliciano
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000821:virology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D015363:Quinolones / Q000494:pharmacology* / Q000633:toxicity; D015533:Transcriptional Activation; D014170:Transformation, Genetic; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects*
chemical_list: D016207:Cytokines; D019253:Proto-Oncogene Proteins c-bcl-2; D015363:Quinolones