title: Short chain fatty acids potently induce latent HIV-1 in T-cells by activating P-TEFb and multiple histone modifications.
abstract: HIV patients with severe periodontitis have high levels of residual virus in their saliva and plasma despite effective therapy (HAART). Multiple short chain fatty acids (SCFAs) from periodontal pathogens reactivate HIV-1 in both Jurkat and primary T-cell models of latency. SCFAs not only activate positive transcription elongation factor b (P-TEFb), which is an essential cellular cofactor for Tat, but can also reverse chromatin blocks by inducing histone modifications. SCFAs simultaneously increase histone acetylation by inhibiting class-1/2 histone deacetylases (HDACs) and decrease repressive histone tri-methylation at the proviral LTR by downregulating expression of the class-3 HDAC sirtuin-1 (SIRT1), and the histone methyltransferases enhancer of Zeste homolog 2 (EZH2) and suppressor of variegation 3-9 homolog 1 (SUV39H1). Our findings provide a mechanistic link between periodontal disease and enhanced HIV-1 replication, and suggest that treatment of periodontal disease, or blocking the activities of SCFAs, will have a therapeutic benefit for HIV patients.
authors.affiliation: Department of Molecular Biology and Microbiology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, United States.
authors.forename: Biswajit
authors.initials: B
authors.lastname: Das
authors.affiliation: Department of Molecular Biology and Microbiology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, United States.
authors.forename: Curtis
authors.initials: C
authors.lastname: Dobrowolski
authors.affiliation: Department of Periodontics, School of Dental Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, United States.
authors.forename: Abdel-Malek
authors.initials: AM
authors.lastname: Shahir
authors.affiliation: Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, United States.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, United States.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, United States.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Sha
authors.affiliation: Department of Periodontics, School of Dental Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, United States.
authors.forename: Nabil F
authors.initials: NF
authors.lastname: Bissada
authors.affiliation: Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, United States.
authors.forename: Aaron
authors.initials: A
authors.lastname: Weinberg
authors.affiliation: Department of Molecular Biology and Microbiology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, United States. Electronic address: jonathan.karn@case.edu.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Karn
authors.affiliation: Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, United States. Electronic address: fxy63@case.edu.
authors.forename: Fengchun
authors.initials: F
authors.lastname: Ye
mesh_terms: D000107:Acetylation; D001419:Bacteria / Q000378:metabolism; D002478:Cells, Cultured; D000071221:Enhancer of Zeste Homolog 2 Protein; D005232:Fatty Acids, Volatile / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D015658:HIV Infections / Q000150:complications / Q000378:metabolism / Q000821:virology; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D008780:Methyltransferases / Q000378:metabolism; D008954:Models, Biological; D010518:Periodontitis / Q000150:complications / Q000378:metabolism / Q000382:microbiology; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D012463:Saliva / Q000378:metabolism / Q000821:virology; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism* / Q000821:virology*; D015533:Transcriptional Activation; D014775:Virus Activation / Q000502:physiology; D017735:Virus Latency / Q000235:genetics / Q000502:physiology*
chemical_list: D005232:Fatty Acids, Volatile; D006657:Histones; D012097:Repressor Proteins; C407843:SUV39H1 protein, human; D008780:Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D042925:Positive Transcriptional Elongation Factor B; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D006655:Histone Deacetylases
keywords: EZH2; HIV-1 transactivation; P-TEFb; SIRT1; Short chain fatty acids