Therapy for Latent HIV-1 Infection: The Role of Histone Deacetylase Inhibitors

McManamy, Mary E Manson; Hakre, Shweta; Verdin, Eric; Margolis, David M.

doi:10.3851/imp2551

Cited by 45 publications

(20 citation statements)

References 54 publications

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“…Paradoxically, these HDACs play opposing roles during latent and lytic viral infections (46). Because of their role in promoting the compact chromatin organization and repression of transcription, these HDACs promote latency of herpesviruses and HIV-1 and have been the target of HDAC inhibitors to reactivate these viruses for getting rid of the infection (47)(48)(49)(50). In contrast, during herpesvirus lytic infections, HDAC1 (and HDAC2) plays an antiviral role by repressing the viral gene transcription and inducing the type I IFN response (44,49,51).…”

Section: Discussionmentioning

confidence: 99%

Influenza A Virus Dysregulates Host Histone Deacetylase 1 That Inhibits Viral Infection in Lung Epithelial Cells

Nagesh

Husain

2016

J Virol

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Viruses dysregulate the host factors that inhibit virus infection. Here, we demonstrate that human enzyme, histone deacetylase 1 (HDAC1) is a new class of host factor that inhibits influenza A virus (IAV) infection, and IAV dysregulates HDAC1 to efficiently replicate in epithelial cells. A time-dependent decrease in HDAC1 polypeptide level was observed in IAV-infected cells, reducing to <50% by 24 h of infection. A further depletion (97%) of HDAC1 expression by RNA interference increased the IAV growth kinetics, increasing it by >3-fold by 24 h and by >6-fold by 48 h of infection. Conversely, overexpression of HDAC1 decreased the IAV infection by >2-fold. Likewise, a time-dependent decrease in HDAC1 activity, albeit with slightly different kinetics to HDAC1 polypeptide reduction, was observed in infected cells. Nevertheless, a further inhibition of deacetylase activity increased IAV infection in a dose-dependent manner. HDAC1 is an important host deacetylase and, in addition to its role as a transcription repressor, HDAC1 has been lately described as a coactivator of type I interferon response. Consistent with this property, we found that inhibition of deacetylase activity either decreased or abolished the phosphorylation of signal transducer and activator of transcription I (STAT1) and expression of interferon-stimulated genes, IFITM3, ISG15, and viperin in IAV-infected cells. Furthermore, the knockdown of HDAC1 expression in infected cells decreased viperin expression by 58% and, conversely, the overexpression of HDAC1 increased it by 55%, indicating that HDAC1 is a component of IAV-induced host type I interferon antiviral response. IMPORTANCEInfluenza A virus (IAV) continues to significantly impact global public health by causing regular seasonal epidemics, occasional pandemics, and zoonotic outbreaks. IAV is among the successful human viral pathogens that has evolved various strategies to evade host defenses, prevent the development of a universal vaccine, and acquire antiviral drug resistance. A comprehensive knowledge of IAV-host interactions is needed to develop a novel and alternative anti-IAV strategy. Host produces a variety of factors that are able to fight IAV infection by employing various mechanisms. However, the full repertoire of anti-IAV host factors and their antiviral mechanisms has yet to be identified. We have identified here a new host factor, histone deacetylase 1 (HDAC1) that inhibits IAV infection. We demonstrate that HDAC1 is a component of host innate antiviral response against IAV, and IAV undermines HDAC1 to limit its role in antiviral response. Influenza A virus (IAV), a prototypic member of family Orthomyxoviridae, has been a successful human respiratory pathogen. IAV has prevented the development of a universal vaccine so far and rendered the currently approved anti-influenza virus drugs almost ineffective. A unique genetic make-up comprising of a segmented RNA genome and a broad host range of humans, birds, pigs, dogs, cats, horses, seals, and bats allows the regular emer...

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Section: Discussionmentioning

confidence: 99%

Influenza A Virus Dysregulates Host Histone Deacetylase 1 That Inhibits Viral Infection in Lung Epithelial Cells

Nagesh

Husain

2016

J Virol

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“…Histone deacetylase inhibitors (HDACi), like valproic acid or voninostat (SAHA), are well suited to the purpose, with the ability to increase histone acetylation of the integrated viral promoter and therefore trigger reactivation of the latent reservoir. This strategy was tried in patients but unfortunately was unsuccessful in eliminating all latent viruses, likely due to only partial activation of the latent reservoir (Archin et al , 2014; Manson McManamy et al , 2014; Rasmussen et al , 2013; Siliciano and Siliciano, 2014). …”

Section: Viral Latency As a Complex Barrier To An Hiv-1 Curementioning

confidence: 99%

Genome editing strategies: potential tools for eradicating HIV-1/AIDS

et al. 2015

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Current therapy for controlling HIV-1 infection and preventing AIDS progression has profoundly decreased viral replication in cells susceptible to HIV-1 infection, but it does not eliminate the low level of viral replication in latently infected cells which contain integrated copies of HIV-1 proviral DNA. There is an urgent need for the development of HIV-1 genome eradication strategies that will lead to a permanent or “sterile” cure of HIV-1/AIDS. In the past few years, novel nuclease-initiated genome editing tools have been developing rapidly, including ZFNs, TALENs, and the CRISPR/Cas9 system. These surgical knives, which can excise any genome, provide a great opportunity to eradicate the HIV-1 genome by targeting highly conserved regions of the HIV-1 long terminal repeats or essential viral genes. Given the time consuming and costly engineering of target-specific ZFNs and TALENs, the RNA-guided endonuclease Cas9 technology has emerged as a simpler and more versatile technology to allow permanent removal of integrated HIV-1 proviral DNA in eukaryotic cells, and hopefully animal models or human patients. The major unmet challenges of this approach at present include inefficient nuclease gene delivery, potential off-target cleavage, and cell-specific genome targeting. Nanoparticle or lentivirus-mediated delivery of next generation Cas9 technologies including nickase or RNA-guided FokI nuclease (RFN) will further improve the potential for genome editing to become a promising approach for curing HIV-1/AIDS.

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“…CD4+ T-cells from individuals on suppressive ART harbor the virus in a latent or minimally active state (reviewed in Ruelas and Greene, 2013). Since viral latency is primarily considered to be regulated by histone architecture, drugs that relax chromatin are being explored for their ability to reactivate the virus from latency (reviewed in Manson McManamy et al 2014). Chromatin modifiers such as vorinostat can reactivate viral latency in in vitro models and there is some evidence for weak activation of the virus in vivo (Archin et al 2012).…”

Section: Obstacles To Elimination Of Myeloid Cell Reservoirsmentioning

confidence: 99%

Role of myeloid cells in HIV-1-host interplay

Stevenson

2014

J. Neurovirol.

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The AIDS Research Field has embarked on a bold mission to cure HIV-1-infected individuals of the virus. To do so, scientists are attempting to identify the reservoirs that support viral persistence in patients on therapy, to understand how viral persistence is regulated and to come up with strategies that interrupt viral persistence and that eliminate the viral reservoirs. Most of the attention regarding the cure of HIV-1 has infection has focused on the CD4+ T-cell reservoir. Investigators are developing tools to probe the CD4+ T-cell reservoirs as well as in vitro systems that provide clues on how to perturb them. By comparison, the myeloid cell, and in particular, the macrophage has received far less attention. As a consequence, there is very little understanding as to the role played by myeloid cells in viral persistence in HIV-1 infected individuals on suppressive therapy. As such, should myeloid cells constitute a viral reservoir, unique strategies may be required for their elimination. This article will overview research that is examining the role of macrophage in virus-host interplay and will discuss features of this interplay that could impact efforts to eliminate myeloid cell reservoirs.

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Therapy for Latent HIV-1 Infection: The Role of Histone Deacetylase Inhibitors

Cited by 45 publications

References 54 publications

Influenza A Virus Dysregulates Host Histone Deacetylase 1 That Inhibits Viral Infection in Lung Epithelial Cells

Influenza A Virus Dysregulates Host Histone Deacetylase 1 That Inhibits Viral Infection in Lung Epithelial Cells

Genome editing strategies: potential tools for eradicating HIV-1/AIDS

Role of myeloid cells in HIV-1-host interplay

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