Histone deacetylases (HDACs) are part of a vast family of enzymes that have crucial roles in numerous biological processes, largely through their repressive influence on transcription. The expression of many HDAC isoforms in eukaryotic cells raises questions about their possible specificity or redundancy, and whether they control global or specific programmes of gene expression. Recent analyses of HDAC knockout mice have revealed highly specific functions of individual HDACs in development and disease. Mutant mice lacking individual HDACs are a powerful tool for defining the functions of HDACs in vivo and the molecular targets of HDAC inhibitors in disease.

The many roles of histone deacetylases in development and physiology: Implications for disease and therapy

To investigate the occurrence of olfactory and gustatory dysfunctions in patients with laboratory-confirmed COVID-19 infection. Patients with laboratory-confirmed COVID-19 infection were recruited from 12 European hospitals. The following epidemiological and clinical outcomes have been studied: age, sex, ethnicity, comorbidities, and general and otolaryngological symptoms. Patients completed olfactory and gustatory questionnaires based on the smell and taste component of the National Health and Nutrition Examination Survey, and the short version of the Questionnaire of Olfactory Disorders-Negative Statements (sQOD-NS). A total of 417 mild-to-moderate COVID-19 patients completed the study (263 females). The most prevalent general symptoms consisted of cough, myalgia, and loss of appetite. Face pain and nasal obstruction were the most disease-related otolaryngological symptoms. 85.6% and 88.0% of patients reported olfactory and gustatory dysfunctions, respectively. There was a significant association between both disorders (p < 0.001). Olfactory dysfunction (OD) appeared before the other symptoms in 11.8% of cases. The sQO-NS scores were significantly lower in patients with anosmia compared with normosmic or hyposmic individuals (p = 0.001). Among the 18.2% of patients without nasal obstruction or rhinorrhea, 79.7% were hyposmic or anosmic. The early olfactory recovery rate was 44.0%. Females were significantly more affected by olfactory and gustatory dysfunctions than males (p = 0.001). Olfactory and gustatory disorders are prevalent symptoms in European COVID-19 patients, who may not have nasal symptoms. The sudden anosmia or ageusia need to be recognized by the international scientific community as important symptoms of the COVID-19 infection.

https://link.springer.com/content/pdf/10.1007/s00405-020-05965-1.pdf

Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study.

Viral infections have detrimental impacts on neurological functions, and even to cause severe neurological damage. Very recently, coronaviruses (CoV), especially severe acute respiratory syndrome CoV 2 (SARS-CoV-2), exhibit neurotropic properties and may also cause neurological diseases. It is reported that CoV can be found in the brain or cerebrospinal fluid. The pathobiology of these neuroinvasive viruses is still incompletely known, and it is therefore important to explore the impact of CoV infections on the nervous system. Here, we review the research into neurological complications in CoV infections and the possible mechanisms of damage to the nervous system.

/pdf/nervous-system-involvement-after-infection-with-covid-19-and-1wvkcokhlc.pdf

Nervous system involvement after infection with COVID-19 and other coronaviruses

https://demystifyingmedicine.od.nih.gov/DM14/2014-02-11/Cell-y2013v155p540.pdf

Replication-Competent Noninduced Proviruses in the Latent Reservoir Increase Barrier to HIV-1 Cure

Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-1) remains a principal obstacle to curing the infection. Inducing the expression of latent genomes within resting CD4(+) T cells is the primary strategy to clear this reservoir. Although histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (also known as vorinostat, VOR) can disrupt HIV-1 latency in vitro, the utility of this approach has never been directly proven in a translational clinical study of HIV-infected patients. Here we isolated the circulating resting CD4(+) T cells of patients in whom viraemia was fully suppressed by antiretroviral therapy, and directly studied the effect of VOR on this latent reservoir. In each of eight patients, a single dose of VOR increased both biomarkers of cellular acetylation, and simultaneously induced an increase in HIV RNA expression in resting CD4(+) cells (mean increase, 4.8-fold). This demonstrates that a molecular mechanism known to enforce HIV latency can be therapeutically targeted in humans, provides proof-of-concept for histone deacetylase inhibitors as a therapeutic class, and defines a precise approach to test novel strategies to attack and eradicate latent HIV infection directly.

/pdf/administration-of-vorinostat-disrupts-hiv-1-latency-in-4cer52vaae.pdf

Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy

http://www-personal.umich.edu/~simeonem/USpaper.pdf

A Methodology For Performing Global Uncertainty And Sensitivity Analysis In Systems Biology

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(05)67098-5.pdf

Depletion of latent HIV-1 infection in vivo: a proof-of-concept study

Virus Infections in the Nervous System

Human immunodeficiency virus type 1 (HIV-1) particle assembly mediated by the viral structural protein Gag occurs predominantly on the plasma membrane (PM). Although it is known that the matrix (MA) domain of Gag plays a major role in PM localization, molecular mechanisms that determine the location of assembly remain to be elucidated. We observed previously that overexpression of polyphosphoinositide 5-phosphatase IV (5ptaseIV) that depletes PM phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P(2)] impairs virus particle production and redirects processed Gag to intracellular compartments. In this study, we examined the impact of PI(4,5)P(2) depletion on the subcellular localization of the entire Gag population using Gag-fluorescent protein chimeras. Upon 5ptaseIV overexpression, in addition to perinuclear localization, Gag also showed a hazy cytosolic signal, suggesting that PI(4,5)P(2) depletion impairs Gag membrane binding. Indeed, Gag was less membrane bound in PI(4,5)P(2)-depleted cells, as assessed by biochemical analysis. These observations are consistent with the hypothesis that Gag interacts with PI(4,5)P(2). To examine a putative Gag interaction with PI(4,5)P(2), we developed an in vitro binding assay using full-length myristoylated Gag and liposome-associated PI(4,5)P(2). Using this assay, we observed that PI(4,5)P(2) significantly enhances liposome binding of wild-type Gag. In contrast, a Gag derivative lacking MA did not require PI(4,5)P(2) for efficient liposome binding. To analyze the involvement of MA in PI(4,5)P(2) binding further, we examined MA basic amino acid substitution mutants. These mutants, previously shown to localize in perinuclear compartments, bound PI(4,5)P(2)-containing liposomes weakly. Altogether, these results indicate that HIV-1 Gag binds PI(4,5)P(2) on the membrane and that the MA basic domain mediates this interaction.

Interaction between the Human Immunodeficiency Virus Type 1 Gag Matrix Domain and Phosphatidylinositol-(4,5)-Bisphosphate Is Essential for Efficient Gag Membrane Binding

Bioinspired organ-level in vitro platforms are emerging as effective technologies for fundamental research, drug discovery, and personalized healthcare. In particular, models for nervous system research are especially important, due to the complexity of neurological phenomena and challenges associated with developing targeted treatment of neurological disorders. Here we introduce an additive manufacturing-based approach in the form of a bioinspired, customizable 3D printed nervous system on a chip (3DNSC) for the study of viral infection in the nervous system. Micro-extrusion 3D printing strategies enabled the assembly of biomimetic scaffold components (microchannels and compartmented chambers) for the alignment of axonal networks and spatial organization of cellular components. Physiologically relevant studies of nervous system infection using the multiscale biomimetic device demonstrated the functionality of the in vitro platform. We found that Schwann cells participate in axon-to-cell viral spread but appear refractory to infection, exhibiting a multiplicity of infection (MOI) of 1.4 genomes per cell. These results suggest that 3D printing is a valuable approach for the prototyping of a customized model nervous system on a chip technology.

Ian B. Hogue

Papers

A Methodology For Performing Global Uncertainty And Sensitivity Analysis In Systems Biology

Depletion of latent HIV-1 infection in vivo: a proof-of-concept study

Virus Infections in the Nervous System

Interaction between the Human Immunodeficiency Virus Type 1 Gag Matrix Domain and Phosphatidylinositol-(4,5)-Bisphosphate Is Essential for Efficient Gag Membrane Binding

3D printed nervous system on a chip