Influenza A virus-induced host caspase and viral PA-X antagonize the antiviral host factor, histone deacetylase 4.

Influenza A virus (IAV) effectively manipulates host machinery to replicate. There is a growing evidence that an optimal acetylation environment in the host cell is favorable to IAV proliferation and vice versa. The histone deacetylases (HDACs), a family of 18 host enzymes classified into four classes, are central to negatively regulating the acetylation level, hence the HDACs would not be favorable to IAV. Indeed, by using the RNAi and overexpression strategies, we found that human HDAC4, a class II member, possesses anti-IAV properties and is a component of host innate antiviral response. We discovered that IAV multiplication was augmented in HDAC4-depleted cells and abated in HDAC4-supplemented cells. Likewise, the expression of IFITM3, ISG15, and viperin, some of the critical markers of host anti-IAV response was abated in HDAC4-depleted cells and augmented in HDAC4-supplemented cells. In turn, IAV strongly antagonizes the HDAC4, by down-regulating its expression both at the mRNA level via viral RNA endonuclease PA-X and at the polypeptide level by inducing its cleavage via host caspase 3 in infected cells. Such HDAC4 polypeptide cleavage resulted in a ∼30 kDa fragment that is also observed in some heterologous systems and may have a significant role in IAV replication.

The Class IV human deacetylase, HDAC11, exhibits anti-influenza A virus properties via its involvement in host innate antiviral response.

Histone deacetylase 11 (HDAC11) is most recently discovered deacetylase. Here, we demonstrate that human HDAC11 exhibits anti-influenza A virus (IAV) properties. We found that knockdown of HDAC11 expression augments IAV growth kinetics in human lung epithelial cells A549 by up to 1 log. One of the ways HDAC11 exerts its anti-IAV function is by being a part of IAV-induced host antiviral response. We found that the kinetics of both IAV- and interferon-induced innate antiviral response is significantly delayed in HDAC11-depleted cells. Further, in the absence of HDAC11 expression, there was a significant decrease in the expression of interferon-stimulated genes-IFITM3, ISG15, and viperin-previously implicated in anti-IAV function. One of the ways IAV antagonises HDAC11 is by downregulating its expression in host cells. We found that there was up to 93% reduction in HDAC11 transcript levels in A549 cells in response to IAV infection. HDAC11 is the smallest HDAC with majority of its polypeptide assigned to catalytic domain. Evolutionarily, it seems to be the least evolved and most closely related to common ancestral HDAC gene(s). Furthermore, HDAC11 has also been described as a deacylase. Therefore, our findings present exciting prospects for further investigations into significance of HDAC11 in virus infections.

Histone Deacetylase 2 Is a Component of Influenza A Virus-Induced Host Antiviral Response.

Host cells produce variety of antiviral factors that create an antiviral state and target various stages of influenza A virus (IAV) life cycle to inhibit infection. However, IAV has evolved various strategies to antagonize those antiviral factors. Recently, we reported that a member of class I host histone deacetylases (HDACs), HDAC1 possesses an anti-IAV function. Herein, we provide evidence that HDAC2, another class I member and closely related to HDAC1 in structure and function, also possesses anti-IAV properties. In turn, IAV, like HDAC1, dysregulates HDAC2, mainly at the polypeptide level through proteasomal degradation to potentially minimize its antiviral effect. We found that IAV downregulated the HDAC2 polypeptide level in A549 cells in an H1N1 strain-independent manner by up to 47%, which was recovered to almost 100% level in the presence of proteasome-inhibitor MG132. A further knockdown in HDAC2 expression by up to 90% via RNA interference augmented the growth kinetics of IAV in A549 cells by more than four-fold after 24 h of infection. Furthermore, the knockdown of HDAC2 expression decreased the IAV-induced phosphorylation of the transcription factor, Signal Transducer and Activator of Transcription I (STAT1) and the expression of interferon-stimulated gene, viperin in infected cells by 41 and 53%, respectively. The role of HDAC2 in viperin expression was analogous to that of HDAC1, but it was not in the phosphorylation of STAT1. This indicated that, like HDAC1, HDAC2 is a component of IAV-induced host innate antiviral response and performs both redundant and non-redundant functions vis-a-vis HDAC1; however, IAV dysregulates them both in a redundant manner.

Drug resistance in influenza A virus: the epidemiology and management.

Influenza A virus (IAV) is the sole cause of the unpredictable influenza pandemics and deadly zoonotic outbreaks and constitutes at least half of the cause of regular annual influenza epidemics in humans. Two classes of anti-IAV drugs, adamantanes and neuraminidase (NA) inhibitors (NAIs) targeting the viral components M2 ion channel and NA, respectively, have been approved to treat IAV infections. However, IAV rapidly acquired resistance against both classes of drugs by mutating these viral components. The adamantane-resistant IAV has established itself in nature, and a majority of the IAV subtypes, especially the most common H1N1 and H3N2, circulating globally are resistant to adamantanes. Consequently, adamantanes have become practically obsolete as anti-IAV drugs. Similarly, up to 100% of the globally circulating IAV H1N1 subtypes were resistant to oseltamivir, the most commonly used NAI, until 2009. However, the 2009 pandemic IAV H1N1 subtype, which was sensitive to NAIs and has now become one of the dominant seasonal influenza virus strains, has replaced the pre-2009 oseltamivir-resistant H1N1 variants. This review traces the epidemiology of both adamantane- and NAI-resistant IAV subtypes since the approval of these drugs and highlights the susceptibility status of currently circulating IAV subtypes to NAIs. Further, it provides an overview of currently and soon to be available control measures to manage current and emerging drug-resistant IAV. Finally, this review outlines the research directions that should be undertaken to manage the circulation of IAV in intermediate hosts and develop effective and alternative anti-IAV therapies.