Lindbergcarstens6210

entry pathway, E30 accumulates in classical early endosomes. Copyright © 2020 American Society for Microbiology.Histone deacetylase inhibitors (HDACi) are the most widely studied HIV latency reversing agents (LRAs). The HDACi suberoylanilidehydroxamic acid (vorinostat, VOR) has been employed in several clinical HIV latency reversal studies as well as in vitro models of HIV latency and shown to effectively induce HIV RNA and protein expression. Despite these findings, response to HDACi can vary, particularly with intermittent dosing, and information is lacking on the relationship between host transcriptional response and HIV latency reversal. Herein, we report on global gene expression responses to VOR and examined the longevity of the transcriptional response in various cellular models. We find many genes are modulated at 6 h post-VOR in HCT116, Jurkat and primary resting CD4 T cells yet return to baseline levels after an 18 h VOR-free period. With repeat exposure to VOR in resting CD4 T cells, we find similar and consistent transcriptional changes 6 h following each serial treatment. In addition, serial exposure in HIly exposures to VOR. Our study provides evidence that VOR induces a consistent level of host cell gene transcription, following intermittent exposure. In addition, a gene signature was identified in response to VOR exposure that was conserved across single and serial exposures both in vitro and in vivo, indicating that VOR can consistently and reproducibly modulate transcriptional host responses. However, as responses to HIV response to HDACis decline over time, other factors modulate viral reactivation in vivo despite robust HDAC activity. The identified host gene VOR biomarkers can be used for monitoring the pharmacodynamic activity of HDAC inhibitors. Copyright © 2020 Maxwell et al.Měnglà virus (MLAV), identified in Rousettus bats, is a phylogenetically distinct member of the family Filoviridae Because the filoviruses Ebola virus (EBOV) and Marburg virus (MARV) modulate host innate immunity, MLAV VP35, VP40 and VP24 proteins were compared with their EBOV and MARV homologs for innate immune pathway modulation. In human and Rousettus cells, MLAV VP35 behaved like EBOV and MARV VP35s, inhibiting virus-induced activation of the interferon (IFN)-β promoter and IRF3 phosphorylation. MLAV VP35 also interacted with PACT, a host protein engaged by EBOV VP35 to inhibit RIG-I signaling. MLAV VP35 also inhibits PKR activation. AZ 628 nmr MLAV VP40 was demonstrated to inhibit type I IFN induced gene expression in human and bat cells. It blocked STAT1 tyrosine phosphorylation induced either by type I IFN or over-expressed Jak1, paralleling MARV VP40. MLAV VP40 also inhibited virus-induced IFNβ promoter activation, a property shared by MARV VP40 and EBOV VP24. A Jak kinase inhibitor did not recapitulate this inhy activities are possessed by MLAV VP35 and VP40, which parallels how MARV blocks IFN responses. However, whereas MARV activates cellular antioxidant responses through an interaction between its VP24 protein and host protein Keap1, MLAV VP24 lacks a Keap1 binding motif and fails to activate this cytoprotective response. These data indicate that MLAV possesses immune suppressing functions that could facilitate human infection. They also support the placement of MLAV in a different genus than either EBOV or MARV. Copyright © 2020 American Society for Microbiology.Human herpesviruses 6A and 6B (HHV-6A and HHV-6B, respectively) are two virus species in the beta herpesvirus subfamily that exhibit T cell tropism. CD46 and CD134 are the cellular receptors for HHV-6A and HHV-6B, respectively. Interestingly, the efficiency of HHV-6A/6B entry is different among different types of target cells despite similar receptor expression levels on these cells. Here, we found that the cellular factor gp96 is expressed on the cell surface and interacts with the viral glycoprotein Q1 (gQ1) during virus entry. gp96 cell surface expression levels are associated with the efficiency of HHV-6A and HHV-6B entry into target cells. Both loss-of-function and gain-of-function experiments indicated that gp96 plays an important role in HHV-6 infection. Our findings provide new insight into the HHV-6 entry process and might suggest novel therapeutic targets for HHV-6 infection.IMPORTANCE Although new clinical importance has been revealed for human herpesviruses 6A and 6B, much is still unknown about the lifecycles of these viruses in target cells. We identified a novel cellular factor, gp96, that is critical for both HHV-6A and -6B entry into host cells. As gp96 can function as an adjuvant in vaccine development for both infectious agents and cancers, it can be a potential therapeutic target for infection by these two viruses. Copyright © 2020 American Society for Microbiology.During all stages of infection HSV-1 expresses viral miRNAs. There are at least 20 confirmed HSV-1 miRNAs, yet the roles of individual miRNAs in the context of viral infection remain largely uncharacterized. We constructed a recombinant virus lacking the sequences for miR-H1-5p and miR-H6-3p (17dmiR-H1/H6). The seed sequences for these miRNAs are antisense to each other and are transcribed from divergent non-coding RNAs in the latency-associated transcript (LAT) promoter region. Comparing phenotypes exhibited by the recombinant virus lacking these miRNAs to the wild-type (17syn+), we found that during acute infection in cell culture 17dmiR-H1/H6 exhibited a modest increase in viral yields. Analysis of pathogenesis in the mouse following footpad infection revealed a slight increase in virulence for 17dmiR-H1/H6 but no significant difference in the establishment or maintenance of latency. Strikingly, explant of latently infected dorsal root ganglia revealed a decreased and delayed reactivation phenotype. Furtheonstrate that deletion of the seed sequences of these miRNAs results in a severe reduction in reactivation of HSV-1 in the mouse and rabbit models. These results suggest a linkage between these miRNAs and reactivation. Copyright © 2020 American Society for Microbiology.Small noncoding RNAs (sncRNA), including microRNA (miR) are expressed by many viruses to provide an additional layer of gene expression regulation. Our work has shown that Varicella-Zoster virus (VZV, HHV3), the human alphaherpesvirus causing varicella and herpes zoster, expresses 24 virally encoded sncRNA (VZVsncRNA) in infected cells Here we demonstrate that several VZVsncRNA can modulate VZV growth, including four VZVscnRNA (VZVsncRNA10, 11, 12,13) that are antisense to VLT, a transcript made in lytic infections and associated with VZV latency. The influence on productive VZV growth and spread was assessed in epithelial cells transfected with locked nucleotide analog antagonists (LNAA). LNAA to the four VZVsncRNA antisense to VLT significantly reduced viral spread and progeny titers of infectious virus, suggesting these sncRNA promoted lytic infection. The LNAA to VZVsncRNA12, encoded in the leader to ORF61, also significantly increased the levels of VLT transcripts. Conversely, overexpression of VZVsncRNA13 using adeno-associated virus consistently increased VZV spread and progeny titers.