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.
Subject(s)
Fatty Acids, Volatile/metabolism , HIV-1/physiology , Histones/metabolism , Positive Transcriptional Elongation Factor B/metabolism , T-Lymphocytes/metabolism , T-Lymphocytes/virology , Virus Latency/physiology , Acetylation , Bacteria/metabolism , Cells, Cultured , Enhancer of Zeste Homolog 2 Protein , Gene Knockdown Techniques , HIV Infections/complications , HIV Infections/metabolism , HIV Infections/virology , HIV Long Terminal Repeat , HIV-1/genetics , HIV-1/pathogenicity , Histone Deacetylases/metabolism , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/physiology , Humans , Jurkat Cells , Methyltransferases/metabolism , Models, Biological , Periodontitis/complications , Periodontitis/metabolism , Periodontitis/microbiology , Polycomb Repressive Complex 2/metabolism , Repressor Proteins/metabolism , Saliva/metabolism , Saliva/virology , Sirtuin 1/antagonists & inhibitors , Sirtuin 1/genetics , Sirtuin 1/metabolism , Transcriptional Activation , Virus Activation/physiology , Virus Latency/geneticsABSTRACT
UNLABELLED: Periodontal pathogens such as Porphyromonas gingivalis and Fusobacterium nucleatum produce five different short-chain fatty acids (SCFAs) as metabolic by-products. We detect significantly higher levels of SCFAs in the saliva of patients with severe periodontal disease. The different SCFAs stimulate lytic gene expression of Kaposi's sarcoma-associated herpesvirus (KSHV) dose dependently and synergistically. SCFAs inhibit class-1/2 histone deacetylases (HDACs) and downregulate expression of silent information regulator-1 (SIRT1). SCFAs also downregulate expression of enhancer of zeste homolog2 (EZH2) and suppressor of variegation 3-9 homolog1 (SUV39H1), which are two histone N-lysine methyltransferases (HLMTs). By suppressing the different components of host epigenetic regulatory machinery, SCFAs increase histone acetylation and decrease repressive histone trimethylations to transactivate the viral chromatin. These new findings provide mechanistic support that SCFAs from periodontal pathogens stimulate KSHV replication and infection in the oral cavity and are potential risk factors for development of oral Kaposi's sarcoma (KS). IMPORTANCE: About 20% of KS patients develop KS lesions first in the oral cavity, while other patients never develop oral KS. It is not known if the oral microenvironment plays a role in oral KS tumor development. In this work, we demonstrate that a group of metabolic by-products, namely, short-chain fatty acids, from bacteria that cause periodontal disease promote lytic replication of KSHV, the etiological agent associated with KS. These new findings provide mechanistic support that periodontal pathogens create a unique microenvironment in the oral cavity that contributes to KSHV replication and development of oral KS.
