scholarly journals 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

2003 ◽  
Vol 77 (13) ◽  
pp. 7244-7253 ◽  
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.

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

Virology ◽  
1999 ◽  
Vol 263 (2) ◽  
pp. 408-417 ◽  
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

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

2005 ◽  
Vol 79 (9) ◽  
pp. 5653-5664 ◽  
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.

scholarly journals The S2 Gene of Equine Infectious Anemia Virus Is Dispensable for Viral Replication In Vitro

1998 ◽  
Vol 72 (10) ◽  
pp. 8344-8348 ◽  
Author(s):  
Feng Li ◽  
Bridget A. Puffer ◽  
Ronald C. Montelaro
Keyword(s):  
Equine Infectious Anemia Virus ◽  
Parental Virus ◽  
Target Cells ◽  
Monocyte Differentiation ◽  
Cell Culture Systems ◽  
Equine Infectious Anemia ◽  
Anemia Virus ◽  
First Time

ABSTRACT Equine infectious anemia virus (EIAV) contains the simplest genome among lentiviruses in that it encodes only three putative regulatory genes (S1, S2, S3) in addition to the canonical gag, pol, and envgenes, presumably reflecting its limited tropism to cells of monocyte/macrophage lineage. Tat and Rev functions have been assigned to S1 and S3, respectively, but the specific function for the S2 gene has yet to be determined. Thus, the function of S2 in virus replication in vitro was investigated by using an infectious molecular viral clone, EIAVUK. Various EIAVUK mutants lackingS2 were constructed, and their replication kinetics were examined in several equine cell culture systems, including the natural in vivo target equine macrophage cells. The EIAV S2 mutants showed replication kinetics similar to those of the parental virus in all of the tested primary and transformed equine cell cultures, without any detectable reversion of mutant genomes. The EIAVUKmutants also showed replication kinetics similar to those of the parental virus in an equine blood monocyte differentiation-maturation system. These results demonstrate for the first time that the EIAVS2 gene is not essential and does not appear to affect virus infection and replication properties in target cells in vitro.

scholarly journals Replication in vitro and in vivo of an equine infectious anemia virus mutant deficient in dUTPase activity.

1995 ◽  
Vol 69 (5) ◽  
pp. 2881-2888 ◽  
Author(s):  
D L Lichtenstein ◽  
K E Rushlow ◽  
R F Cook ◽  
M L Raabe ◽  
C J Swardson ◽  
...  
Keyword(s):  
Equine Infectious Anemia Virus ◽  
Equine Infectious Anemia ◽  
Virus Mutant ◽  
Anemia Virus

scholarly journals Characterization of Equine Infectious Anemia Virus Long Terminal Repeat QuasispeciesIn VitroandIn Vivo

2018 ◽  
Vol 92 (8) ◽  
Author(s):  
Xue-Feng Wang ◽  
Qiang Liu ◽  
Yu-Hong Wang ◽  
Shuai Wang ◽  
Jie Chen ◽  
...  
Keyword(s):  
Long Terminal Repeat ◽  
Systematic Study ◽  
Equine Infectious Anemia Virus ◽  
Virulent Strain ◽  
Attenuated Virus ◽  
Equine Infectious Anemia ◽  
Anemia Virus ◽  
Over Time

ABSTRACTThe equine infectious anemia virus (EIAV) attenuated vaccine was developed by long-term passaging of a field-isolated virulent strain in cross-species hosts, followed by successive cultivation in cellsin vitro. To explore the molecular mechanism underlying the evolution of the EIAV attenuated vaccine, a systematic study focusing on long-terminal-repeat (LTR) variation in numerous virus strains ranging from virulent EIAV to attenuated EIAV was performed over time bothin vitroandin vivo. Two hypervariable regions were identified within the U3 region in the enhancer region (EHR) and the negative regulatory element (NRE) and within the R region in the transcription start site (TSS) and the Tat-activating region (TAR). Among these sites, variation in the U3 region resulted in the formation of additional transcription factor binding sites; this variation of thein vitro-adapted strains was consistent with the loss of pathogenicity. Notably, the same LTR variation pattern was observed bothin vitroandin vivo. Generally, the LTR variation in both the attenuated virus and the virulent strain fluctuated over timein vivo. Interestingly, the attenuated-virus-specific LTR variation was also detected in horses infected with the virulent strain, supporting the hypothesis that the evolution of an attenuated virus might have involved branching from EIAV quasispecies. This hypothesis was verified by phylogenetic analysis. The present systematic study examining the molecular evolution of attenuated EIAV from EIAV quasispecies may provide an informative model reflecting the evolution of similar lentiviruses.IMPORTANCEThe attenuated EIAV vaccine was the first lentiviral vaccine used to successfully control for equine infectious anemia in China. This vaccine provides an important reference for studying the relationship between EIAV gene variation and changes in biological characteristics. Importantly, the vaccine provides a model for the investigation of lentiviral quasispecies evolution. This study followed the “natural” development of the attenuated EIAV vaccine by use of a systematic analysis of LTR evolutionin vitroandin vivo. The results revealed that the increase in LTR variation with passaging was accompanied by a decrease in virulence, which indicated that LTR variability might parallel the attenuation of virulence. Interestingly, the attenuated-virus-specific LTR variation was also detected in virulent-strain-infected horses, a finding consistent with those of previous investigations ofgp90andS2evolution. Therefore, we present a hypothesis that the evolution of the attenuated virus may involve branching from EIAV quasispecies presentin vivo.

scholarly journals Discerning an Effective Balance between Equine Infectious Anemia Virus Attenuation and Vaccine Efficacy

2005 ◽  
Vol 79 (5) ◽  
pp. 2666-2677 ◽  
Author(s):  
Jodi K. Craigo ◽  
Feng Li ◽  
Jonathan D. Steckbeck ◽  
Shannon Durkin ◽  
Laryssa Howe ◽  
...  
Keyword(s):  
Vaccine Efficacy ◽  
Equine Infectious Anemia Virus ◽  
Protective Efficacy ◽  
Accessory Gene ◽  
Live Attenuated Vaccine ◽  
Virus Challenge ◽  
Proviral Clone ◽  
Immune Correlates ◽  
Equine Infectious Anemia ◽  
Anemia Virus

ABSTRACT Among the diverse experimental vaccines evaluated in various animal lentivirus models, live attenuated vaccines have proven to be the most effective, thus providing an important model for examining critical immune correlates of protective vaccine immunity. We previously reported that an experimental live attenuated vaccine for equine infectious anemia virus (EIAV), based on mutation of the viral S2 accessory gene, elicited protection from detectable infection by virulent virus challenge (F. Li et al., J. Virol. 77:7244-7253, 2003). To better understand the critical components of EIAV vaccine efficacy, we examine here the relationship between the extent of virus attenuation, the maturation of host immune responses, and vaccine efficacy in a comparative study of three related attenuated EIAV proviral vaccine strains: the previously described EIAVUKΔS2 derived from a virulent proviral clone, EIAVUKΔS2/DU containing a second gene mutation in the virulent proviral clone, and EIAVPRΔS2 derived from a reference avirulent proviral clone. Inoculations of parallel groups of eight horses resulted in relatively low levels of viral replication (average of 102 to 103 RNA copies/ml) and a similar maturation of EIAV envelope-specific antibody responses as determined in quantitative and qualitative serological assays. However, experimental challenge of the experimentally immunized horses by our standard virulent EIAVPV strain by using a low-dose multiple exposure protocol (three inoculations with 10 median horse infective doses, administered intravenously) revealed a marked difference in the protective efficacy of the various attenuated proviral vaccine strains that was evidently associated with the extent of vaccine virus attenuation, time of viral challenge, and the apparent maturation of virus-specific immunity.

scholarly journals The determination of in vivo envelope-specific cell-mediated immune responses in equine infectious anemia virus-infected ponies

2012 ◽  
Vol 148 (3-4) ◽  
pp. 302-310 ◽  
Author(s):  
Chong Liu ◽  
Frank R. Cook ◽  
Sheila J. Cook ◽  
Jodi K. Craigo ◽  
Deborah L. Even ◽  
...  
Keyword(s):  
Immune Responses ◽  
Equine Infectious Anemia Virus ◽  
Specific Cell ◽  
Equine Infectious Anemia ◽  
Anemia Virus

scholarly journals Equine Infectious Anemia Virus Resists the Antiretroviral Activity of Equine APOBEC3 Proteins through a Packaging-Independent Mechanism

2008 ◽  
Vol 82 (23) ◽  
pp. 11889-11901 ◽  
Author(s):  
Hal P. Bogerd ◽  
Rebecca L. Tallmadge ◽  
J. Lindsay Oaks ◽  
Susan Carpenter ◽  
Bryan R. Cullen
Keyword(s):  
Equine Infectious Anemia Virus ◽  
Cytidine Deaminase ◽  
Biological Activities ◽  
Single Copy ◽  
Virion Incorporation ◽  
Equine Infectious Anemia ◽  
Anemia Virus ◽  
Hiv 1

ABSTRACT Equine infectious anemia virus (EIAV), uniquely among lentiviruses, does not encode a vif gene product. Other lentiviruses, including human immunodeficiency virus type 1 (HIV-1), use Vif to neutralize members of the APOBEC3 (A3) family of intrinsic immunity factors that would otherwise inhibit viral infectivity. This suggests either that equine cells infected by EIAV in vivo do not express active A3 proteins or that EIAV has developed a novel mechanism to avoid inhibition by equine A3 (eA3). Here, we demonstrate that horses encode six distinct A3 proteins, four of which contain a single copy of the cytidine deaminase (CDA) consensus active site and two of which contain two CDA motifs. This represents a level of complexity previously seen only in primates. Phylogenetic analysis of equine single-CDA A3 proteins revealed two proteins related to human A3A (hA3A), one related to hA3C, and one related to hA3H. Both equine double-CDA proteins are similar to hA3F and were named eA3F1 and eA3F2. Analysis of eA3F1 and eA3F2 expression in vivo shows that the mRNAs encoding these proteins are widely expressed, including in cells that are natural EIAV targets. Both eA3F1 and eA3F2 inhibit retrotransposon mobility, while eA3F1 is a potent inhibitor of a Vif-deficient HIV-1 mutant and induces extensive editing of HIV-1 reverse transcripts. However, both eA3F1 and eA3F2 are weak inhibitors of EIAV. Surprisingly, eA3F1 and eA3F2 were packaged into EIAV and HIV-1 virions as effectively as hA3G, although only the latter inhibited EIAV infectivity. Moreover, all three proteins bound both the HIV-1 and EIAV nucleocapsid protein specifically in vitro. It therefore appears that EIAV has evolved a novel mechanism to specifically neutralize the biological activities of the cognate eA3F1 and eA3F2 proteins at a step subsequent to virion incorporation.

scholarly journals Replication Ability in Vitro and in Vivo of Equine Infectious Anemia Virus Avirulent Japanese Strain

Virology ◽  
2000 ◽  
Vol 266 (1) ◽  
pp. 129-139 ◽  
Author(s):  
Yong-Hui Zheng ◽  
Hiroshi Sentsui ◽  
Miyuki Sugita ◽  
Takaaki Nakaya ◽  
Masahiko Kishi ◽  
...  
Keyword(s):  
Equine Infectious Anemia Virus ◽  
Japanese Strain ◽  
Equine Infectious Anemia ◽  
Anemia Virus
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