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

Lichtenstein, Drew L.; Craigo, Jodi K.; Leroux, Caroline; Rushlow, K E; Cook, R. F.; Cook, Sheila J.; Issel, Charles J.; Montelaro, Ronald C.

doi:10.1006/viro.1999.9921

Cited by 20 publications

(16 citation statements)

References 37 publications

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“…In vivo analysis of the proviral challenge strains by experimental infections of equids confirmed characteristic EIAV pathogenesis and virulence properties. Standard viral replication kinetics, including the induction of acute disease and progression to chronic disease, were observed for all three strains (19,32,34). Interestingly, assays of antibody responses elicited by experimental infections with variant challenge viruses indicated distinct neutralization phenotypes for the individual variant envelopes; each variant challenge virus was neutralized by immune serum from homologous virus infections, but not from heterologous virus infections (SI Fig.…”

Section: Development Of Variant Challenge Strainsmentioning

confidence: 94%

Envelope variation as a primary determinant of lentiviral vaccine efficacy

Craigo

Zhang

Barnes

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Lentiviral envelope antigenic variation and associated immune evasion are believed to present major obstacles to effective vaccine development. Although this perception is widely assumed by the scientific community, there is, to date, no rigorous experimental data assessing the effect of increasing levels of lentiviral Env variation on vaccine efficacy. It is our working hypothesis that Env is, in fact, a primary determinant of vaccine effectiveness. We previously reported that a successful experimental attenuated equine infectious anemia virus vaccine, derived by mutation of the viral S2 accessory gene, provided 100% protection from disease after virulent virus challenge. Here, we sought to comprehensively test our hypothesis by challenging vaccinated animals with proviral strains of defined, increasing Env variation, using variant envelope SU genes that arose naturally during experimental infection of ponies with equine infectious anemia virus. The reference attenuated vaccine combined with these variant Env challenge strains facilitated evaluation of the protection conferred by ancestral immunogens, because the Env of the attenuated vaccine is a direct ancestor to the variant proviral strain Envs. The results demonstrated that ancestral Env proteins did not impart broad levels of protection against challenge. Furthermore, the results displayed a significant inverse linear correlation of Env divergence and protection from disease. This study demonstrates potential obstacles to the use of single isolate ancestral Env immunogens. Finally, these findings reveal that relatively minor Env variation can pose a substantial challenge to lentiviral vaccine immunity, even when attenuated vaccines are used that, to date, achieve the highest levels of vaccine protection.ancestral immunogen ͉ equine infectious anemia virus ͉ lentivirus

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Section: Development Of Variant Challenge Strainsmentioning

confidence: 94%

Envelope variation as a primary determinant of lentiviral vaccine efficacy

Craigo

Zhang

Barnes

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, the MA-1 variant of EIAV wyoming was selected by in vitro adaptation in equine dermal cells [14]. LTR variants have been shown to be rapidly eliminated in vivo [29,91]. LTR variations are associated with in vitro adaptation to nonnatural target cells such as non-equine cells or fibroblasts; in vivo replication probably requires a rapid adaptation of the LTR.…”

Section: Viral Evolution In Infected Animalsmentioning

confidence: 99%

Equine Infectious Anemia Virus (EIAV): what has HIV?s country cousin got to tell us?

2004

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-Equine Infectious Anemia Virus (EIAV) is a lentivirus, of the Retrovirus family, with an almost worldwide distribution, infecting equids. It causes a persistent infection characterized by recurring febrile episodes associating viremia, fever, thrombocytopenia, and wasting symptoms. The disease is experimentally reproducible by inoculation of Shetland ponies or horses with EIAV pathogenic strains. Among lentiviruses, EIAV is unique in that, despite a rapid virus replication and antigenic variation, most animals progress from a chronic stage characterized by recurring peaks of viremia and fever to an asymptomatic stage of infection. The inapparent carriers remain infective for life, as demonstrated by experimental transfer of blood to naive animals. The understanding of the correlates of this immune control is of great interest in defining vaccine strategies. Research on EIAV, this "country cousin" of HIV (Human Immunodeficiency Virus), over the last five decades has produced some interesting results on natural immunological control of lentivirus replication and disease and on the nature and role of virus variation in persistence and pathogenesis. These studies are of interest in the context of HIV and efforts to develop a vaccine. This review will focus on some of the most recent results. equine infectious anemia virus / lentivirus / equids / vaccine / viral evolution

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“…Previous studies have retrospectively identified alterations in EIAV LTR enhancer sequences that are associated with longterm passage in macrophages or leukocyte cultures (56) or fibroblasts (6,25,27,43). These changes include loss and gain of transcription factor binding motifs (36).…”

Section: Discussionmentioning

confidence: 99%

“…Some studies have identified extensive EIAV LTR enhancer changes including multiple nucleotide insertions or deletions (27,57), whereas other studies have found more modest changes (6,43). LTR alterations that are associated with fibroblast tropism have been correlated with the alteration of LTR activity in a cellspecific manner (43,57); however, other reports suggest that the LTR changes found in tissue culture-derived isolates are not associated with cell-specific activity in vitro (25).…”

Section: Discussionmentioning

confidence: 99%

“…Sequence variation throughout the HIV long terminal repeat (LTR) between and within different clades of virus is documented; however, in general, nucleotide variation is limited within the HIV enhancer/promoter proximal region that usually consists of two NF-B and three Sp1 sites (52). In contrast to HIV, the LTR enhancer region of equine infectious anemia virus (EIAV) is one of the most variable regions of the EIAV genome in tissue culture isolates and different field isolates (6,25,36,43). A study that examined seven in vivo isolates demonstrated that 45% of the nucleotide positions within the LTR enhancer varied between the isolates whereas little to no variation was found in the rest of the LTR (36).…”

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confidence: 99%

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

Maury

Thompson

Jones

et al. 2005

J Virol

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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 EIAV wyo 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 EIAV wyo 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 EIAV wyo LTR was evolutionarily stable in vivo.

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

Cited by 20 publications

References 37 publications

Envelope variation as a primary determinant of lentiviral vaccine efficacy

Envelope variation as a primary determinant of lentiviral vaccine efficacy

Equine Infectious Anemia Virus (EIAV): what has HIV?s country cousin got to tell us?

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

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