Wild-type equine infectious anemia virus replicates in vivo predominantly in tissue macrophages, not in peripheral blood monocytes.

ABSTRACT Lentiviruses exist in vivo as a population of related, nonidentical genotypes, commonly referred to as quasispecies. The quasispecies structure is characteristic of complex adaptive systems and contributes to the high rate of evolution in lentiviruses that confounds efforts to develop effective vaccines and antiviral therapies. Here, we describe analyses of genetic data from longitudinal studies of genetic variation in a lentivirus regulatory protein, Rev, over the course of disease in ponies experimentally infected with equine infectious anemia virus. As observed with other lentivirus data, the Rev variants exhibited a quasispecies character. Phylogenetic and partition analyses suggested that the Rev quasispecies comprised two distinct subpopulations that coexisted during infection. One subpopulation appeared to accumulate changes in a linear, time-dependent manner, while the other evolved radially from a common variant. Over time, the two subpopulations cycled in predominance coincident with changes in the disease state, suggesting that the two groups differed in selective advantage. Transient expression assays indicated the two populations differed significantly in Rev nuclear export activity. Chimeric proviral clones containing Rev genotypes representative of each population differed in rate and overall level of virus replication in vitro. The coexistence of genetically distinct viral subpopulations that differ in phenotype provides great adaptability to environmental changes within the infected host. A quasispecies model with multiple subpopulations may provide additional insight into the nature of lentivirus reservoirs and the evolution of antigenic and drug-resistant variants.

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Is the Success of Cefazolin plus Ertapenem in Methicillin-Susceptible Staphylococcus aureus Bacteremia Based on Release of Interleukin 1-beta?

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02166-21 ◽

2022 ◽

Author(s):

Dan Smelter ◽

Mary Hayney ◽

George Sakoulas ◽

Warren Rose

Keyword(s):

Staphylococcus Aureus ◽

Peripheral Blood ◽

Interleukin 1 ◽

Interleukin 1 Beta ◽

Blood Monocytes ◽

Salvage Regimen ◽

Peripheral Blood Monocytes ◽

Staphylococcus Aureus Bacteremia

Cefazolin and ertapenem has been shown to be an effective salvage regimen for refractory methicillin-susceptible Staphylococcus aureus bacteremia. Our findings suggest cefazolin plus ertapenem in vitro stimulates interleukin-1β release from peripheral blood monocytes both with and without S. aureus presence. This IL-1β augmentation was primarily driven by ertapenem. These findings support further exploration of cefazolin plus ertapenem in MSSA bacteremia and may partially explain its marked potency in vivo despite modest synergy in vitro .

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AP-1 (Activated Protein-1) Transcription Factor JunD Regulates Ischemia/Reperfusion Brain Damage via IL-1β (Interleukin-1β)

Stroke ◽

10.1161/strokeaha.118.023739 ◽

2019 ◽

Vol 50 (2) ◽

pp. 469-477 ◽

Cited By ~ 10

Author(s):

Candela Diaz-Cañestro ◽

Martin F. Reiner ◽

Nicole R. Bonetti ◽

Luca Liberale ◽

Mario Merlini ◽

...

Keyword(s):

Ischemic Stroke ◽

Brain Injury ◽

Acute Ischemic Stroke ◽

Peripheral Blood ◽

Ischemia Reperfusion ◽

Interleukin 1Β ◽

Blood Monocytes ◽

Peripheral Blood Monocytes

Background and Purpose— Inflammation is a major pathogenic component of ischemia/reperfusion brain injury, and as such, interventions aimed at inhibiting inflammatory mediators promise to be effective strategies in stroke therapy. JunD—a member of the AP-1 (activated protein-1) family of transcription factors—was recently shown to regulate inflammation by targeting IL (interleukin)-1β synthesis and macrophage activation. The purpose of the present study was to assess the role of JunD in ischemia/reperfusion-induced brain injury. Methods— WT (wild type) mice randomly treated with either JunD or scramble (control) siRNA were subjected to 45 minutes of transient middle cerebral artery occlusion followed by 24 hours of reperfusion. Stroke size, neurological deficit, plasma/brain cytokines, and oxidative stress determined by 4-hydroxynonenal immunofluorescence staining were evaluated 24 hours after reperfusion. Additionally, the role of IL-1β was investigated by treating JunD siRNA mice with an anti–IL-1β monoclonal antibody on reperfusion. Finally, JunD expression was assessed in peripheral blood monocytes isolated from patients with acute ischemic stroke. Results— In vivo JunD knockdown resulted in increased stroke size, reduced neurological function, and increased systemic inflammation, as confirmed by higher neutrophil count and lymphopenia. Brain tissue IL-1β levels were augmented in JunD siRNA mice as compared with scramble siRNA, whereas no difference was detected in IL-6, TNF-α (tumor necrosis factor-α), and 4-hydroxynonenal levels. The deleterious effects of silencing of JunD were rescued by treating mice with an anti–IL-1β antibody. In addition, JunD expression was decreased in peripheral blood monocytes of patients with acute ischemic stroke at 6 and 24 hours after onset of stroke symptoms compared with sex- and age-matched healthy controls. Conclusions— JunD blunts ischemia/reperfusion-induced brain injury via suppression of IL-1β.

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Development of a capture ELISA to determine kinetics of soluble CD25 following in vitro and in vivo stimulation of duck peripheral blood monocytes

Veterinary Immunology and Immunopathology ◽

10.1016/j.vetimm.2010.11.021 ◽

2011 ◽

Vol 140 (1-2) ◽

pp. 102-109 ◽

Cited By ~ 5

Author(s):

Zhenyu Huang ◽

Jie Fang ◽

Jianyou Gu ◽

Yan Yan ◽

Jiyong Zhou

Keyword(s):

Peripheral Blood ◽

Blood Monocytes ◽

Peripheral Blood Monocytes ◽

Capture Elisa ◽

Soluble Cd25 ◽

Kinetics Of ◽

Stimulation Of

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nef-deleted HIV-1 inhibits phagocytosis by monocyte-derived macrophages in vitro but not by peripheral blood monocytes in vivo

AIDS ◽

10.1097/00002030-200105250-00002 ◽

2001 ◽

Vol 15 (8) ◽

pp. 945-955 ◽

Cited By ~ 17

Author(s):

Katherine Kedzierska ◽

Johnson Mak ◽

Anthony Jaworowski ◽

Alison Greenway ◽

Antoniette Violo ◽

...

Keyword(s):

Peripheral Blood ◽

Blood Monocytes ◽

Peripheral Blood Monocytes ◽

Hiv 1

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Effects of Long Terminal Repeat Sequence Variation on Equine Infectious Anemia Virus Replication in Vitro and in Vivo

Virology ◽

10.1006/viro.1999.9921 ◽

1999 ◽

Vol 263 (2) ◽

pp. 408-417 ◽

Cited By ~ 14

Author(s):

Drew L. Lichtenstein ◽

Jodi K. Craigo ◽

Caroline Leroux ◽

Keith E. Rushlow ◽

R.Frank Cook ◽

...

Keyword(s):

Long Terminal Repeat ◽

Virus Replication ◽

Sequence Variation ◽

Equine Infectious Anemia Virus ◽

Repeat Sequence ◽

Equine Infectious Anemia ◽

Anemia Virus ◽

Terminal Repeat Sequence

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Antibody Escape Kinetics of Equine Infectious Anemia Virus Infection of Horses

Journal of Virology ◽

10.1128/jvi.00137-15 ◽

2015 ◽

Vol 89 (13) ◽

pp. 6945-6951 ◽

Cited By ~ 4

Author(s):

Elissa J. Schwartz ◽

Seema Nanda ◽

Robert H. Mealey

Keyword(s):

Neutralizing Antibodies ◽

Equine Infectious Anemia Virus ◽

Wild Type Virus ◽

Type Virus ◽

Wild Type ◽

Fitness Costs ◽

Equine Infectious Anemia ◽

Anemia Virus ◽

Kinetics Of ◽

Virus Fitness

Lentivirus escape from neutralizing antibodies (NAbs) is not well understood. In this work, we quantified antibody escape of a lentivirus, using antibody escape data from horses infected with equine infectious anemia virus. We calculated antibody blocking rates of wild-type virus, fitness costs of mutant virus, and growth rates of both viruses. These quantitative kinetic estimates of antibody escape are important for understanding lentiviral control by antibody neutralization and in developing NAb-eliciting vaccine strategies.

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Evolution of the Equine Infectious Anemia Virus Long Terminal Repeat during the Alteration of Cell Tropism

Journal of Virology ◽

10.1128/jvi.79.9.5653-5664.2005 ◽

2005 ◽

Vol 79 (9) ◽

pp. 5653-5664 ◽

Cited By ~ 17

Author(s):

Wendy Maury ◽

Robert J. Thompson ◽

Quentin Jones ◽

Sarahann Bradley ◽

Tara Denke ◽

...

Keyword(s):

Long Terminal Repeat ◽

Equine Infectious Anemia Virus ◽

Terminal Repeat ◽

Binding Motif ◽

Cell Tropism ◽

Transcription Factor Binding Motif ◽

Equine Infectious Anemia ◽

Anemia Virus

ABSTRACT Equine infectious anemia virus (EIAV) is a lentivirus with in vivo cell tropism primarily for tissue macrophages; however, in vitro the virus can be adapted to fibroblasts and other cell types. Tropism adaptation is associated with both envelope and long terminal repeat (LTR) changes, and findings strongly suggest that these regions of the genome influence cell tropism and virulence. Furthermore, high levels of genetic variation have been well documented in both of these genomic regions. However, specific EIAV nucleotide or amino acid changes that are responsible for cell tropism changes have not been identified. A study was undertaken with the highly virulent, macrophage-tropic strain of virus EIAVwyo to identify LTR changes associated with alterations in cell tropism. We found the stepwise generation of a new transcription factor binding motif within the enhancer that was associated with adaptation of EIAV to endothelial cells and fibroblasts. An LTR that contained the new motif had enhanced transcriptional activity in fibroblasts, whereas the new site did not alter LTR activity in a macrophage cell line. This finding supports a previous prediction that selection for new LTR genetic variants may be a consequence of cell-specific selective pressures. Additional investigations of the EIAVwyo LTR were performed in vivo to determine if LTR evolution could be detected over the course of a 3-year infection. Consistent with previous in vivo findings, we observed no changes in the enhancer region of the LTR over that time period, indicating that the EIAVwyo LTR was evolutionarily stable in vivo.

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A Live Attenuated Equine Infectious Anemia Virus Proviral Vaccine with a Modified S2 Gene Provides Protection from Detectable Infection by Intravenous Virulent Virus Challenge of Experimentally Inoculated Horses

Journal of Virology ◽

10.1128/jvi.77.13.7244-7253.2003 ◽

2003 ◽

Vol 77 (13) ◽

pp. 7244-7253 ◽

Cited By ~ 40

Author(s):

Feng Li ◽

Jodi K. Craigo ◽

Laryssa Howe ◽

Jonathan D. Steckbeck ◽

Sheila Cook ◽

...

Keyword(s):

Immune Responses ◽

Equine Infectious Anemia Virus ◽

High Dose ◽

Accessory Gene ◽

Virus Challenge ◽

Equine Infectious Anemia ◽

Anemia Virus ◽

Vaccine Immunity

ABSTRACT Previous evaluations of inactivated whole-virus and envelope subunit vaccines to equine infectious anemia virus (EIAV) have revealed a broad spectrum of efficacy ranging from highly type-specific protection to severe enhancement of viral replication and disease in experimentally immunized equids. Among experimental animal lentivirus vaccines, immunizations with live attenuated viral strains have proven most effective, but the vaccine efficacy has been shown to be highly dependent on the nature and severity of the vaccine virus attenuation. We describe here for the first time the characterization of an experimental attenuated proviral vaccine, EIAVUKΔS2, based on inactivation of the S2 accessory gene to down regulate in vivo replication without affecting in vitro growth properties. The results of these studies demonstrated that immunization with EIAVUKΔS2 elicited mature virus-specific immune responses by 6 months and that this vaccine immunity provided protection from disease and detectable infection by intravenous challenge with a reference virulent biological clone, EIAVPV. This level of protection was observed in each of the six experimental horses challenged with the reference virulent EIAVPV by using a low-dose multiple-exposure protocol (three administrations of 10 median horse infectious doses [HID50], intravenous) designed to mimic field exposures and in all three experimentally immunized ponies challenged intravenously with a single inoculation of 3,000 HID50. In contrast, naïve equids subjected to the low- or high-dose challenge develop a detectable infection of challenge virus and acute disease within several weeks. Thus, these data demonstrate that the EIAV S2 gene provides an optimal site for modification to achieve the necessary balance between attenuation to suppress virulence and replication potential to sufficiently drive host immune responses to produce vaccine immunity to viral exposure.

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