The Effect of JAK1/2 Inhibitors on HIV Reservoir Using Primary Lymphoid Cell Model of HIV Latency

Front Immunol. 2021 Aug 31:12:720697. doi: 10.3389/fimmu.2021.720697. eCollection 2021.

Abstract

HIV eradication is hindered by the existence of latent HIV reservoirs in CD4+ T cells. Therapeutic strategies targeting latent cells are required to achieve a functional cure, however the study of latently infected cells from HIV infected persons is extremely challenging due to the lack of biomarkers that uniquely characterize them. In this study, the dual reporter virus HIVGKO was used to investigate latency establishment and maintenance in lymphoid-derived CD4+ T cells. Single cell technologies to evaluate protein expression, host gene expression, and HIV transcript expression were integrated to identify and analyze latently infected cells. FDA-approved, JAK1/2 inhibitors were tested in this system as a potential therapeutic strategy to target the latent reservoir. Latent and productively infected tonsillar CD4+ T cells displayed similar activation profiles as measured by expression of CD69, CD25, and HLADR, however latent cells showed higher CXCR5 expression 3 days post-infection. Single cell analysis revealed a small set of genes, including HIST1-related genes and the inflammatory cytokine, IL32, that were upregulated in latent compared to uninfected and productively infected cells suggesting a role for these molecular pathways in persistent HIV infection. In vitro treatment of HIV-infected CD4+ T cells with physiological concentrations of JAK1/2 inhibitors, ruxolitinib and baricitinib, used in clinical settings to target inflammation, reduced latent and productive infection events when added 24 hr after infection and blocked HIV reactivation from latent cells. Our methods using an established model of HIV latency and lymphoid-derived cells shed light on the biology of latency in a crucial anatomical site for HIV persistence and provides key insights about repurposing baricitinib or ruxolitinib to target the HIV reservoir.

Keywords: HIV; JAK-STAT signaling pathway; LRA (latency reversing agent); latency; scRNAseq; tonsil.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes / drug effects*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / virology*
  • Gene Expression Profiling
  • HIV Infections / immunology
  • HIV Infections / metabolism
  • HIV Infections / virology*
  • HIV-1 / drug effects*
  • HIV-1 / physiology*
  • Humans
  • Immunophenotyping
  • Janus Kinase 1 / antagonists & inhibitors
  • Janus Kinase 2 / antagonists & inhibitors
  • Janus Kinase Inhibitors / pharmacology*
  • Janus Kinase Inhibitors / therapeutic use
  • Lymphocyte Activation / immunology
  • Palatine Tonsil
  • STAT Transcription Factors / metabolism
  • Signal Transduction / drug effects
  • Single-Cell Analysis
  • Transcriptome
  • Virus Activation / drug effects
  • Virus Latency / drug effects*
  • Virus Replication / drug effects

Substances

  • Janus Kinase Inhibitors
  • STAT Transcription Factors
  • JAK1 protein, human
  • JAK2 protein, human
  • Janus Kinase 1
  • Janus Kinase 2