Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Stem-loop binding protein is a multifaceted cellular regulator of HIV-1 replication
Ming Li, … , Michelle A. Lally, Bharat Ramratnam
Ming Li, … , Michelle A. Lally, Bharat Ramratnam
Published July 25, 2016
Citation Information: J Clin Invest. 2016;126(8):3117-3129. https://doi.org/10.1172/JCI82360.
View: Text | PDF
Research Article AIDS/HIV

Stem-loop binding protein is a multifaceted cellular regulator of HIV-1 replication

  • Text
  • PDF
Abstract

A rare subset of HIV-1–infected individuals is able to maintain plasma viral load (VL) at low levels without antiretroviral treatment. Identifying the mechanisms underlying this atypical response to infection may lead to therapeutic advances for treating HIV-1. Here, we developed a proteomic analysis to compare peripheral blood cell proteomes in 20 HIV-1–infected individuals who maintained either high or low VL with the aim of identifying host factors that impact HIV-1 replication. We determined that the levels of multiple histone proteins were markedly decreased in cohorts of individuals with high VL. This reduction was correlated with lower levels of stem-loop binding protein (SLBP), which is known to control histone metabolism. Depletion of cellular SLBP increased promoter engagement with the chromatin structures of the host gene high mobility group protein A1 (HMGA1) and viral long terminal repeat (LTR), which led to higher levels of HIV-1 genomic integration and proviral transcription. Further, we determined that TNF-α regulates expression of SLBP and observed that plasma TNF-α levels in HIV-1–infected individuals correlated directly with VL levels and inversely with cellular SLBP levels. Our findings identify SLBP as a potentially important cellular regulator of HIV-1, thereby establishing a link between histone metabolism, inflammation, and HIV-1 infection.

Authors

Ming Li, Lynne D. Tucker, John M. Asara, Collins K. Cheruiyot, Huafei Lu, Zhijin J. Wu, Michael C. Newstein, Mark S. Dooner, Jennifer Friedman, Michelle A. Lally, Bharat Ramratnam

×

Figure 6

TNF-α downregulates SLBP expression.

Options: View larger image (or click on image) Download as PowerPoint
TNF-α downregulates SLBP expression.
(A) In vitro TNF-α treatment decrea...
(A) In vitro TNF-α treatment decreased SLBP expression. CEM cells were treated with TNF-α (30 ng/ml). At 24 and 48 hours after treatment, SLBP protein and RNA levels were reduced by approximately 40% as quantified by Western blot (left panel) and RT-PCR (right panel), respectively. ACTB was used as the loading control (n = 3 biologic replicates). Student’s t test; *P < 0.05; error bars represent ± SD. (B) Treatment of CEM cells by TNF-α with subsequent HIV-1 infection led to significantly higher (~4-fold) levels of viral unspliced RNA in comparison with untreated cells or those simultaneously treated with an SLBP expression vector (TNF-α+SLBP). Note that superphysiologic expression of SLBP significantly decreased the HIV-1 enabling activity of TNF-α by 30% (n = 3 biologic replicates). One-way ANOVA with post hoc Tukey’s test; *P < 0.05, **P < 0.01; error bars represent ± SD. (C) Plasma levels of TNF-α in the original cohorts (n = 27) were quantified by ELISA and were significantly elevated in the high-VL group. Mann-Whitney test; *P < 0.05; error bars represent ± SEM. (D) The number of study subjects was expanded to include HIV-1–uninfected individuals (n = 23), those on suppressive antiretroviral therapy (ART) (n = 20), and additional individuals with VL less than 2,000 (n = 21) and VL greater than 10,000 (n = 26). Intracellular SLBP expression was approximately 40% higher (*P < 0.05) in the low-VL versus the high-VL group. SLBP protein levels in PBMCs were quantified by ELISA for each subject. One-way ANOVA with post hoc Tukey’s test; *P < 0.05; error bars represent ± SEM. (E) A proposed TNF-α/SLBP circuit that impacts HIV-1 integration and transcription. TNF-α induced by proinflammatory stimuli decreases cellular SLBP levels, leading to enhanced HIV-1 integration and proviral transcription via an SLBP-mediated increase in viral and HMGA1 promoter accessibility.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts