Transient Reversal of Episome Silencing Precedes VP16-Dependent Transcription during Reactivation of Latent HSV-1 in Neurons

Herpes simplex virus type-1 (HSV-1) establishes latency in peripheral neurons, creating a permanent source of recurrent infections. The latent genome is assembled into chromatin and lytic cycle genes are silenced. Processes that orchestrate reentry into productive replication (reactivation) remain poorly understood. We have used latently infected cultures of primary superior cervical ganglion (SCG) sympathetic neurons to profile viral gene expression following a defined reactivation stimulus. Lytic genes are transcribed in two distinct phases, differing in their reliance on protein synthesis, viral DNA replication and the essential initiator protein VP16. The first phase does not require viral proteins and has the appearance of a transient, widespread de-repression of the previously silent lytic genes. This allows synthesis of viral regulatory proteins including VP16, which accumulate in the cytoplasm of the host neuron. During the second phase, VP16 and its cellular cofactor HCF-1, which is also predominantly cytoplasmic, concentrate in the nucleus where they assemble an activator complex on viral promoters. The transactivation function supplied by VP16 promotes increased viral lytic gene transcription leading to the onset of genome amplification and the production of infectious viral particles. Thus regulated localization of de novo synthesized VP16 is likely to be a critical determinant of HSV-1 reactivation in sympathetic neurons

Epigenetic Regulation of Histone H3 Serine 10 Phosphorylation Status by HCF-1 Proteins in C. elegans and Mammalian Cells

BACKGROUND: The human herpes simplex virus (HSV) host cell factor HCF-1 is a transcriptional coregulator that associates with both histone methyl- and acetyltransferases, and a histone deacetylase and regulates cell proliferation and division. In HSV-infected cells, HCF-1 associates with the viral protein VP16 to promote formation of a multiprotein-DNA transcriptional activator complex. The ability of HCF proteins to stabilize this VP16-induced complex has been conserved in diverse animal species including Drosophila melanogaster and Caenorhabditis elegans suggesting that VP16 targets a conserved cellular function of HCF-1. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the role of HCF proteins in animal development, we have characterized the effects of loss of the HCF-1 homolog in C. elegans, called Ce HCF-1. Two large hcf-1 deletion mutants (pk924 and ok559) are viable but display reduced fertility. Loss of Ce HCF-1 protein at reduced temperatures (e.g., 12 degrees C), however, leads to a high incidence of embryonic lethality and early embryonic mitotic and cytokinetic defects reminiscent of mammalian cell-division defects upon loss of HCF-1 function. Even when viable, however, at normal temperature, mutant embryos display reduced levels of phospho-histone H3 serine 10 (H3S10P), a modification implicated in both transcriptional and mitotic regulation. Mammalian cells with defective HCF-1 also display defects in mitotic H3S10P status. CONCLUSIONS/SIGNIFICANCE: These results suggest that HCF-1 proteins possess conserved roles in the regulation of cell division and mitotic histone phosphorylation

Persistent Staphylococcus aureus Colonization Is Not a Strongly Heritable Trait in Amish Families

About 20% of adults are persistently colonized with S. aureus in the anterior nares. Host genetic factors could contribute susceptibility to this phenotype. The objective of this study was to determine whether the phenotype of persistent S. aureus colonization aggregates in family members who live in different households. Healthy adults and their eligible same sex siblings who lived in different households were recruited from the Old Order Amish of Lancaster, Pennsylvania. All participants had two cultures of the anterior nares to determine if they were persistently colonized with S. aureus. Three hundred and ninety eight participants finished the study, of whom 166 were index cases and 232 were siblings of index cases. Eighteen per cent (71/398) of all participants and 17% (29/166) of index cases were persistently colonized with S. aureus. Twenty two per cent (8/36) of siblings of persistently colonized index cases were persistently colonized with S. aureus compared to 17% (34/196) of siblings of non-persistently colonized index cases, yielding a prevalence rate ratio of 1.28 (95% CI: 0.65–2.54, p = 0.64) and sibling relative risk of 1.25 (95% CI: 0.65–2.38, p = 0.51). The heritability of persistent colonization was 0.19±0.21 (p = 0.31). Persistent S. aureus colonization does not strongly aggregate in Amish family members in different households and heritability is low, suggesting that environmental factors or acquired host factors are more important than host genetic factors in determining persistent S. aureus colonization in this community

The B-Cell Specific Transcription Factor, Oct-2, Promotes Epstein-Barr Virus Latency by Inhibiting the Viral Immediate-Early Protein, BZLF1

The Epstein-Barr virus (EBV) latent-lytic switch is mediated by the BZLF1 immediate-early protein. EBV is normally latent in memory B cells, but cellular factors which promote viral latency specifically in B cells have not been identified. In this report, we demonstrate that the B-cell specific transcription factor, Oct-2, inhibits the function of the viral immediate-early protein, BZLF1, and prevents lytic viral reactivation. Co-transfected Oct-2 reduces the ability of BZLF1 to activate lytic gene expression in two different latently infected nasopharyngeal carcinoma cell lines. Furthermore, Oct-2 inhibits BZLF1 activation of lytic EBV promoters in reporter gene assays, and attenuates BZLF1 binding to lytic viral promoters in vivo. Oct-2 interacts directly with BZLF1, and this interaction requires the DNA-binding/dimerization domain of BZLF1 and the POU domain of Oct-2. An Oct-2 mutant (Δ262–302) deficient for interaction with BZLF1 is unable to inhibit BZLF1-mediated lytic reactivation. However, an Oct-2 mutant defective for DNA-binding (Q221A) retains the ability to inhibit BZLF1 transcriptional effects and DNA-binding. Importantly, shRNA-mediated knockdown of endogenous Oct-2 expression in several EBV-positive Burkitt lymphoma and lymphoblastoid cell lines increases the level of lytic EBV gene expression, while decreasing EBNA1 expression. Moreover, treatments which induce EBV lytic reactivation, such as anti-IgG cross-linking and chemical inducers, also decrease the level of Oct-2 protein expression at the transcriptional level. We conclude that Oct-2 potentiates establishment of EBV latency in B cells

Effects of childhood socioeconomic position on subjective health and health behaviours in adulthood: how much is mediated by adult socioeconomic position?

<p>Abstract</p> <p>Background</p> <p>Adult socioeconomic position (SEP) is one of the most frequently hypothesised indirect pathways between childhood SEP and adult health. However, few studies that explore the indirect associations between childhood SEP and adult health systematically investigate the mediating role of multiple individual measures of adult SEP for different health outcomes. We examine the potential mediating role of individual measures of adult SEP in the associations of childhood SEP with self-rated health, self-reported mental health, current smoking status and binge drinking in adulthood.</p> <p>Methods</p> <p>Data came from 10,010 adults aged 25-64 years at Wave 3 of the Survey of Family, Income and Employment in New Zealand. The associations between childhood SEP (assessed using retrospective information on parental occupation) and self-rated health, self-reported psychological distress, current smoking status and binge drinking were determined using logistic regression. Models were adjusted individually for the mediating effects of education, household income, labour market activity and area deprivation.</p> <p>Results</p> <p>Respondents from a lower childhood SEP had a greater odds of being a current smoker (OR 1.70 95% CI 1.42-2.03), reporting poorer health (OR 1.82 95% CI 1.39-2.38) or higher psychological distress (OR 1.60 95% CI 1.20-2.14) compared to those from a higher childhood SEP. Two-thirds to three quarters of the association of childhood SEP with current smoking (78%), and psychological distress (66%) and over half the association with poor self-rated health (55%) was explained by educational attainment. Other adult socioeconomic measures had much smaller mediating effects.</p> <p>Conclusions</p> <p>This study suggests that the association between childhood SEP and self-rated health, psychological distress and current smoking in adulthood is largely explained through an indirect socioeconomic pathway involving education. However, household income, area deprivation and labour market activity are still likely to be important as they are intermediaries in turn, in the socioeconomic pathway between education and health.</p

Entry of Herpes Simplex Virus Type 1 (HSV-1) into the Distal Axons of Trigeminal Neurons Favors the Onset of Nonproductive, Silent Infection

Following productive, lytic infection in epithelia, herpes simplex virus type 1 (HSV-1) establishes a lifelong latent infection in sensory neurons that is interrupted by episodes of reactivation. In order to better understand what triggers this lytic/latent decision in neurons, we set up an organotypic model based on chicken embryonic trigeminal ganglia explants (TGEs) in a double chamber system. Adding HSV-1 to the ganglion compartment (GC) resulted in a productive infection in the explants. By contrast, selective application of the virus to distal axons led to a largely nonproductive infection that was characterized by the poor expression of lytic genes and the presence of high levels of the 2.0-kb major latency-associated transcript (LAT) RNA. Treatment of the explants with the immediate-early (IE) gene transcriptional inducer hexamethylene bisacetamide, and simultaneous co-infection of the GC with HSV-1, herpes simplex virus type 2 (HSV-2) or pseudorabies virus (PrV) helper virus significantly enhanced the ability of HSV-1 to productively infect sensory neurons upon axonal entry. Helper-virus-induced transactivation of HSV-1 IE gene expression in axonally-infected TGEs in the absence of de novo protein synthesis was dependent on the presence of functional tegument protein VP16 in HSV-1 helper virus particles. After the establishment of a LAT-positive silent infection in TGEs, HSV-1 was refractory to transactivation by superinfection of the GC with HSV-1 but not with HSV-2 and PrV helper virus. In conclusion, the site of entry appears to be a critical determinant in the lytic/latent decision in sensory neurons. HSV-1 entry into distal axons results in an insufficient transactivation of IE gene expression and favors the establishment of a nonproductive, silent infection in trigeminal neurons