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Epigenetics & HIV

Dalibor Miklík, Filip Šenigl, Jiří Hejnar
Individual groups of retroviruses and retroviral vectors differ in their integration site preference and interaction with the host genome. Hence, immediately after infection genome-wide distribution of integrated proviruses is non-random. During long-term in vitro or persistent in vivo infection, the genomic position and chromatin environment of the provirus affects its transcriptional activity. Thus, a selection of long-term stably expressed proviruses and elimination of proviruses, which have been gradually silenced by epigenetic mechanisms, helps in the identification of genomic compartments permissive for proviral transcription...
March 8, 2018: Viruses
Vinay Kumar, Joshua Mansfield, Rong Fan, Andrew MacLean, Jian Li, Mahesh Mohan
Intestinal epithelial barrier dysfunction is a well-known sequela of HIV/SIV infection that persists despite antiretroviral therapy. Although inflammation is a triggering factor, the underlying molecular mechanisms remain unknown. Emerging evidence suggests that epithelial barrier function is epigenetically regulated by inflammation-induced microRNAs (miRNAs). Accordingly, we profiled and characterized miRNA/mRNA expression exclusively in colonic epithelium and identified 46 differentially expressed miRNAs (20 upregulated and 26 downregulated) in chronically SIV-infected rhesus macaques ( Macaca mulatta )...
March 7, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Guochun Jiang, Don Nguyen, Nancie M Archin, Steven A Yukl, Gema Méndez-Lagares, Yuyang Tang, Maher M Elsheikh, George R Thompson, Dennis J Hartigan-O'Connor, David M Margolis, Joseph K Wong, Satya Dandekar
Eradication of HIV-1 (HIV) is hindered by stable viral reservoirs. Viral latency is epigenetically regulated. While the effects of histone acetylation and methylation at the HIV long-terminal repeat (LTR) have been described, our knowledge of the proviral epigenetic landscape is incomplete. We report that a previously unrecognized epigenetic modification of the HIV LTR, histone crotonylation, is a regulator of HIV latency. Reactivation of latent HIV was achieved following the induction of histone crotonylation through increased expression of the crotonyl-CoA-producing enzyme acyl-CoA synthetase short-chain family member 2 (ACSS2)...
February 19, 2018: Journal of Clinical Investigation
Xiaolei Wang, Huanbin Xu
The production of high-affinity and broadly neutralizing antibodies plays a key role in the defense against pathogens. These antibody responses require effective germinal center (GC) reaction within anatomical niches of GCs, where follicular helper T (Tfh) cells provide cognate help to B cells for T cell-dependent antibody responses. Emerging evidences indicate that GC reaction in normal state and perhaps establishment of latent Tfh cell reservoir in HIV/SIV infection are tightly regulated by epigenetic histone modifications, which are responsible for activating or silencing chromatin...
2018: Frontiers in Immunology
Sheraz Khan, Mazhar Iqbal, Muhammad Tariq, Shahid M Baig, Wasim Abbas
HIV-1 latency allows the virus to persist until reactivation, in a transcriptionally silent form in its cellular reservoirs despite the presence of effective cART. Such viral persistence represents a major barrier to HIV eradication since treatment interruption leads to rebound plasma viremia. Polycomb group (PcG) proteins have recently got a considerable attention in regulating HIV-1 post-integration latency as they are involved in the repression of proviral gene expression through the methylation of histones...
2018: Clinical Epigenetics
Oded Danziger, Tal Pupko, Eran Bacharach, Marcelo Ehrlich
Malignancy-induced alterations to cytokine signaling in tumor cells differentially regulate their interactions with the immune system and oncolytic viruses. The abundance of inflammatory cytokines in the tumor microenvironment suggests that such signaling plays key roles in tumor development and therapy efficacy. The JAK-STAT axis transduces signals of interleukin-6 (IL-6) and interferons (IFNs), mediates antiviral responses, and is frequently altered in prostate cancer (PCa) cells. However, how activation of JAK-STAT signaling with different cytokines regulates interactions between oncolytic viruses and PCa cells is not known...
2018: Frontiers in Immunology
Pinar Erkekoglu, Didem Oral, Ming-Wei Chao, Belmar Kocer-Gumusel
The development of hepatocellular carcinoma (HCC) is a multistep process. In HCC, progressive and morphologically distinct preneoplastic lesions/alterations associated with chronic liver injury, inflammation, hepatocellular degeneration/regeneration, necrosis, and small-cell dysplasia can be observed. The incidence of HCC exhibits regional and ethnic differences. Several cytotoxic and DNA-damaging chemicals are suggested to be the underlying causes of HCC-for example, acrylamide, perfluorooctanoic acid (PFOA), polychlorinated biphenyls (PCBs), benzo(a)pyrene (BaP), perfluorinated chemicals (PFCs), vinyl chloride monomer (VCM), and dietary contaminants (aflatoxins, ochratoxins)...
2017: Journal of Environmental Pathology, Toxicology and Oncology
Daniela Boehm, Melanie Ott
A successful HIV cure strategy may require reversing HIV latency to purge hidden viral reservoirs or enhancing HIV latency to permanently silence HIV transcription. Epigenetic modifying agents show promise as antilatency therapeutics in vitro and ex vivo, but also affect other steps in the viral life cycle. In this review, we summarize what we know about cellular DNA and protein methyltransferases (PMTs) as well as demethylases involved in HIV infection. We describe the biology and function of DNA methyltransferases, and their controversial role in HIV infection...
November 2017: AIDS Research and Human Retroviruses
Dimitra Peppa
Human cytomegalovirus (HCMV) has been closely associated with the human race across evolutionary time. HCMV co-infection is nearly universal in human immunodeficiency virus-1 (HIV-1)-infected individuals and remains an important cofactor in HIV-1 disease progression even in the era of effective antiretroviral treatment. HCMV infection has been shown to have a broad and potent influence on the human immune system and has been linked with the discovery and characterization of adaptive natural killer (NK) cells...
2017: Frontiers in Immunology
T Christensen
Several lines of investigation have provided strong indications for an association between the immune-mediated, neurologic disease multiple sclerosis (MS) and human endogenous retroviruses (HERVs). Whether the relationship is causal is yet to be established. Endogenous retroviruses are pathogenic-in other species than the human. Several aspects of the activation and involvement of specific HERV families (HERV-H/F and HERV-W/MSRV) have been documented, both for cells in the periphery and in the central nervous system...
November 2017: Acta Neurologica Scandinavica
George R Young, Sandra N Terry, Lara Manganaro, Alvaro Cuesta-Dominguez, Gintaras Deikus, Dabeiba Bernal-Rubio, Laura Campisi, Ana Fernandez-Sesma, Robert Sebra, Viviana Simon, Lubbertus C F Mulder
Endogenous retroviruses (ERVs) occupy extensive regions of the human genome. Although many of these retroviral elements have lost their ability to replicate, those whose insertion took place more recently, such as the HML-2 group of HERV-K elements, still retain intact open reading frames and the capacity to produce certain viral RNA and/or proteins. Transcription of these ERVs is, however, tightly regulated by dedicated epigenetic control mechanisms. Nonetheless, it has been reported that some pathologic states, such as viral infections and certain cancers, coincide with ERV expression suggesting transcriptional reawakening is possible...
October 18, 2017: Journal of Virology
Cari F Kessing, Christopher C Nixon, Chuan Li, Perry Tsai, Hiroshi Takata, Guillaume Mousseau, Phong T Ho, Jenna B Honeycutt, Mohammad Fallahi, Lydie Trautmann, J Victor Garcia, Susana T Valente
HIV-1 Tat activates viral transcription and limited Tat transactivation correlates with latency establishment. We postulated a "block-and-lock" functional cure approach based on properties of the Tat inhibitor didehydro-Cortistatin A (dCA). HIV-1 transcriptional inhibitors could block ongoing viremia during antiretroviral therapy (ART), locking the HIV promoter in persistent latency. We investigated this hypothesis in human CD4(+) T cells isolated from aviremic individuals. Combining dCA with ART accelerates HIV-1 suppression and prevents viral rebound after treatment interruption, even during strong cellular activation...
October 17, 2017: Cell Reports
Heng Li, Huimin Lu, Wei Tang, Jianping Zuo
Methionine cycle plays an essential role in regulating many cellular events, especially transmethylation reactions, incorporating the methyl donor S-adenosylmethionine (SAM). The transmethylations and substances involved in the cycle have shown complicated effects and mechanisms on immunocytes developments and activations, and exert crucial impacts on the pathological processes in immune disorders. Areas covered: Methionine cycle has been considered as an effective means of drug developments. This review discussed the role of methionine cycle in immune responses and summarized the potential therapeutic strategies based on the cycle, including SAM analogs, methyltransferase inhibitors, S-adenosylhomocysteine hydrolase (SAHH) inhibitors, adenosine receptors specific agonists or antagonists and homocysteine (Hcy)-lowering reagents, in treating human immunodeficiency virus (HIV) infections, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), systemic sclerosis (SSc) and other immune disorders...
August 23, 2017: Expert Opinion on Therapeutic Targets
Uri Mbonye, Jonathan Karn
Although potent combination antiretroviral therapy can effectively block viral replication in the host, human immunodeficiency virus (HIV) persists due to the existence of latent but replication-competent proviruses residing primarily in a very small population of resting memory CD4(+) T cells. Viral latency is established when the expression of the autoregulatory viral trans-activating factor Tat is reduced to subthreshold levels. The absence of Tat reduces HIV transcription and protein production to levels that make the host cell invisible to the immune system and refractory to antiretroviral treatment...
September 29, 2017: Annual Review of Virology
Kaori Asamitsu, Takashi Okamoto
Human immunodeficiency virus type (HIV) transcription is crucial for its life cycle and is primarily involved in the maintenance of viral latency. HIV transcription is regulated by both viral and cellular transcription factors. Numerous epigenetic factors, as well as transcriptional suppressor proteins, play major roles in the maintenance of transcriptional silencing of viral gene expression from the proviral DNA. Once inducible transcription factors such as nuclear factor B are activated through extracellular signaling, viral latency is terminated and transcription from the silenced proviral DNA is initiated...
July 10, 2017: Current Pharmaceutical Design
Vivek Naranbhai, Mary Carrington
This review aims to provide a summary of current knowledge of host genetic effects on human immunodeficiency virus (HIV) disease. Mapping of simple single nucleotide polymorphisms (SNP) has been largely successful in HIV, but more complex genetic associations involving haplotypic or epigenetic variation, for example, remain elusive. Mechanistic insights explaining SNP associations are incomplete, but continue to be forthcoming. The number of robust immunogenetic correlates of HIV is modest and their discovery mostly predates the genome-wide era...
August 2017: Immunogenetics
Anne-Marie W Turner, David M Margolis
The formation of a latent reservoir of Human Immunodeficiency Virus (HIV) infection hidden from immune clearance remains a significant obstacle to approaches to eradicate HIV infection. Towards an understanding of the mechanisms of HIV persistence, there is a growing body of work implicating epigenetic regulation of chromatin in establishment and maintenance of this latent reservoir. Here we discuss recent advances in the field of chromatin regulation, specifically in our understanding of the histone code, and how these discoveries relate to our current knowledge of the chromatin mechanisms linked to HIV transcriptional repression and the reversal of latency...
June 2017: Yale Journal of Biology and Medicine
Yijun Zhang, Hui Zhang
Recent studies reveal that some nuclear microRNAs (miRNA) and synthesized siRNAs target gene promoters to activate gene transcription (RNAa). Interestingly, our group identified a novel HIV-1-encoded miRNA, miR-H3, which targets specifically the core promoter TATA box of HIV-1 and activates viral gene expression. Depletion of miR-H3 significantly impaired the replication of HIV-1. miR-H3 mimics could activate viruses from CD4(+) T cells isolated from patients receiving suppressive highly active antiretroviral therapy, which is very intriguing for reducing HIV-1 latent reservoir...
2017: Advances in Experimental Medicine and Biology
Zheng Zhang, Bryan C Nikolai, Leah A Gates, Sung Yun Jung, Edward B Siwak, Bin He, Andrew P Rice, Bert W O'Malley, Qin Feng
In eukaryotic cells, the gene expression status is strictly controlled by epigenetic modifications on chromatin. The repressive status of chromatin largely contributes to HIV latency. Studies have shown that modification of histone H3K27 acts as a key molecular switch for activation or suppression of many cellular genes. In this study, we found that K27-acetylated histone H3 specifically recruited Super Elongation Complex (SEC), the transcriptional elongation complex essential for HIV-1 long terminal repeat (LTR)-mediated and general cellular transcription...
September 19, 2017: Nucleic Acids Research
Camila Schoueri Colaço, Adriano Reis de Matos, Martha Silva Estrêla, Maurício Cristiano Rocha-Júnior, Kátia Kaori Otaguiri, Evandra Strazza Rodrigues, Osvaldo Massaiti Takayanagui, Dimas Tadeu Covas, Simone Kashima, Fabio Pittella Silva, Rodrigo Haddad
Approximately 5% of human T-cell leukemia virus type 1 (HTLV-1)-infected individuals will develop one of the HTLV-1-related diseases, such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) or adult T-cell leukemia. However, the mechanisms responsible for the appearance of symptoms have not been fully clarified. It is believed that viral factors, host genetic and epigenetic mechanisms are implicated in this process. Studies have shown the involvement of histone methyltransferases in retrovirus infection, but no study observed their expression in HTLV-1-infected patients...
June 12, 2017: Archives of Virology
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