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

• Published in: The Journal of clinical investigation 2016-08, Vol.126 (8), p.3117-3129
• Main Authors: Li, Ming, Tucker, Lynne D, Asara, John M, Cheruiyot, Collins K, Lu, Huafei, Wu, Zhijin J, Newstein, Michael C, Dooner, Mark S, Friedman, Jennifer, Lally, Michelle A, Ramratnam, Bharat
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; AIDS; American Recovery & Reinvestment Act 2009-US; Biomedical research; Candidates; Cell Cycle; Chromatin - metabolism; Data processing; Experiments; Family medical history; Genetic aspects; Genetic transcription; Genomes; HeLa Cells; Histones - metabolism; HIV infection; HIV Infections - metabolism; HIV-1 - physiology; HMGA1a Protein - metabolism; Humans; Infections; Inflammation; Lentivirus; Leukocytes, Mononuclear - metabolism; mRNA Cleavage and Polyadenylation Factors - metabolism; Nuclear Proteins - metabolism; Plasma; Promoter Regions, Genetic; Protein Domains; Proteins; Proteome; Retroviridae; Statistical analysis; Studies; Tumor Necrosis Factor-alpha - metabolism; Viral infections; Viral Load; Virus Replication
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI82360

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.