FIV establishes a latent infection in feline peripheral blood CD4+ T lymphocytes in vivo during the asymptomatic phase of infection

Murphy, Brian G; Vapniarsky, Natalia; Hillman, C.; Castillo, Diego; McDonnel, Samantha J.; Moore, Peter F.; Luciw, Paul A.; Sparger, Ellen E.

doi:10.1186/1742-4690-9-12

Cited by 30 publications

(102 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…At time of purchase, the kittens ranged in age from 4 to 5 months and were housed in the Feline Research Laboratory of the Center for Companion Animal Health, UC Davis. Four kittens were intramuscularly inoculated with FIV-C-Pgmr viral inoculums (kittens 165, 184, 187 and 186) and monitored as described previously (Murphy et al, 2012). Two control kittens (183 and 185) were mock-inoculated with 1 ml of sterile culture media.…”

Section: Methodsmentioning

confidence: 99%

“…Our laboratory has established a model of lentiviral cellular latency in experimentally FIV-infected specific pathogen free (SPF) cats during the asymptomatic phase of infection (Murphy et al, 2012). SPF cats infected with a biological isolate of FIV clade C (Pgmr) for approximately 3 years have an estimated proviral load of 1 infected peripheral CD4 T cell in approximately 10 3 peripheral CD4 T cells (McDonnel et al, 2012b).…”

Section: Introductionmentioning

confidence: 99%

“…A single nucleotide mutation within the FIV-C U3 AP-1 site was previously shown to abrogate transcription in a β galactosidase reporter gene assay (Murphy et al, 2012). This AP-1 mutation was found to be present in the proviral DNA of CD4 T cells isolated from all of the FIV-infected cats.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Peripheral immunophenotype and viral promoter variants during the asymptomatic phase of feline immunodeficiency virus infection

2014

View full text Add to dashboard Cite

Feline immunodeficiency virus (FIV)-infected cats enter a clinically asymptomatic phase during chronic infection. Despite the lack of overt clinical disease, the asymptomatic phase is characterized by persistent immunologic impairment. In the peripheral blood obtained from cats experimentally infected with FIV-C for approximately 5 years, we identified a persistent inversion of the CD4/CD8 ratio. We cloned and sequenced the FIV-C long terminal repeat containing the viral promoter from cells infected with the inoculating virus and from in vivo-derived peripheral blood mononuclear cells and CD4 T cells isolated at multiple time points throughout the asymptomatic phase. Relative to the inoculating virus, viral sequences amplified from cells isolated from all of the infected animals demonstrated multiple single nucleotide mutations and a short deletion within the viral U3, R and U5 regions. A transcriptionally inactivating proviral mutation in the U3 promoter AP-1 site was identified at multiple time points from all of the infected animals but not within cell-associated viral RNA. In contrast, no mutations were identified within the sequence of the viral dUTPase gene amplified from PBMC isolated at approximately 5 years post-infection relative to the inoculating sequence. The possible implications of these mutations to viral pathogenesis are discussed.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Peripheral immunophenotype and viral promoter variants during the asymptomatic phase of feline immunodeficiency virus infection

2014

View full text Add to dashboard Cite

show abstract

“…While the detection and quantification of these various viral components can provide supportive evidence of viral replication, they do not ultimately prove a cell's ability to produce infectious virus. The 'gold standard assay' for the identification of replication-competent and infectious lentiviral reservoir cells is the ex vivo viral outgrowth assay (VOA) which has been used extensively for investigation of HIV-1 latency in humans [111] and in our laboratory for detection of cells containing transcriptionally silent infectious provirus in cats chronically infected with FIV [84,92]. For assessment of virus infection by VOA, an enriched (purified) cell type such as CD4+ T cells are obtained from an infected individual and are cultured ex vivo.…”

Section: Fiv Latencymentioning

confidence: 99%

“…Different cohorts of naturally and experimentally infected cats have demonstrated either undetectable or consistently detectable plasma viraemia during the asymptomatic phase, which may be due to differences in viral strains, inoculating dose, age of the animal or other factors [7,84,98,104,[115][116][117][118]. The cellular mechanisms involved in FIV latency have been identified in both in vitro and in vivo infection systems [52,84,[119][120][121][122]. McDonnel et al reported that peripheral blood-derived CD4+ T cells latently infected with replication-competent, infectious virus were infrequent (estimated at approximately 1 cell in 10 5 peripheral CD4+ T cells).…”

Section: Fiv Latencymentioning

confidence: 99%

Central and peripheral reservoirs of feline immunodeficiency virus in cats: a review

Eckstrand

Sparger

Murphy

2017

Journal of General Virology

View full text Add to dashboard Cite

Infection with feline immunodeficiency virus (FIV), a lentivirus similar to human immunodeficiency virus (HIV), results in lifelong viral persistence and progressive immunopathology in the cat. FIV has the ability to infect and produce infectious virus in a number of different cell types. FIV provirus can also be maintained in a replication-competent but transcriptionally quiescent state, facilitating viral persistence over time. Immediately after the initial infection, FIV infection quickly disseminates to many anatomical compartments within the host including lymphoid organs, gastrointestinal tract and brain. Collectively, the anatomic and cellular compartments that harbour FIV provirus constitute the viral reservoir and contain foci of both ongoing viral replication and transcriptionally restricted virus that may persist over time. The relative importance of the different phenotypes observed for infected cells, anatomic compartment, replication status and size of the reservoir represent crucial areas of investigation for developing effective viral suppression and eradication therapies. In this review, we discuss what is currently known about FIV reservoirs, and emphasize the utility of the FIV-infected cat as a model for the HIV-infected human.

show abstract

Treatment of chronically FIV-infected cats with suberoylanilide hydroxamic acid

2014

View full text Add to dashboard Cite

Feline immunodeficiency virus (FIV) is a naturally-occurring, large animal model of lentiviral-induced immunodeficiency syndrome, and has been used as a model of HIV pathogenesis and therapeutic interventions. HIV reservoirs in the form of latent virus remain the primary roadblock to viral eradication and cure, and FIV has been previously established an animal model of lentiviral latency. The goal of this study was to determine whether administration of the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) to aviremic, chronically FIV-infected cats would induce latent viral reactivation in vivo. A proof-of-concept experiment in a Transwell co-culture system demonstrated the ability of SAHA to reactivate latent virus which was replication competent and able to infect naïve cells. Oral SAHA (250 mg/m2) was administered with food to four asymptomatic, experimentally FIV-infected cats and one uninfected control cat, and a limited pharmacokinetic and pharmacodynamic analysis was performed. A statistically significant increase in cell-associated FIV RNA was detected in the cat with the greatest serum SAHA exposure, and cell-free viral RNA was detected at one time point in the three cats that achieved the highest levels of SAHA in serum. Interestingly, there was a significant decrease in viral DNA burden at 2 hours post drug administration in the same three cats. Though the sample size is small and the drug response was modest, this study provides evidence that in vivo treatment of FIV-infected cats with the HDACi SAHA can induce viral transcriptional reactivation, which may be dependent upon the concentration of SAHA achieved in blood. Importantly, alternative putative antilatency therapy drugs, and multimodal drug combinations, could be studied in this in vivo system. The FIV/cat model provides a unique opportunity to test novel therapeutic interventions aimed at eradicating latent virus in vivo.

show abstract

FIV establishes a latent infection in feline peripheral blood CD4+ T lymphocytes in vivo during the asymptomatic phase of infection

Cited by 30 publications

References 56 publications

Peripheral immunophenotype and viral promoter variants during the asymptomatic phase of feline immunodeficiency virus infection

Peripheral immunophenotype and viral promoter variants during the asymptomatic phase of feline immunodeficiency virus infection

Central and peripheral reservoirs of feline immunodeficiency virus in cats: a review

Treatment of chronically FIV-infected cats with suberoylanilide hydroxamic acid

Contact Info

Product

Resources

About