Treatment of chronically FIV-infected cats with suberoylanilide hydroxamic acid

Samantha J. McDonnel, Molly L. Liepnieks, Brian G Murphy

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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 h 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.

Original languageEnglish (US)
Pages (from-to)74-78
Number of pages5
JournalAntiviral Research
Volume108
Issue number1
DOIs
StatePublished - 2014

Fingerprint

Feline Immunodeficiency Virus
Cats
Histone Deacetylase Inhibitors
Therapeutics
Viruses
Animal Models
HIV
Satellite Viruses
vorinostat
Viral DNA
Viral RNA
Drug Combinations
Coculture Techniques
Viral Load
Serum
Pharmaceutical Preparations
Sample Size
Pharmacokinetics
RNA
Drug Therapy

Keywords

  • Animal model
  • Antilatency therapy
  • FIV
  • HDAC inhibitor
  • HIV
  • SAHA

ASJC Scopus subject areas

  • Virology
  • Pharmacology
  • Medicine(all)

Cite this

Treatment of chronically FIV-infected cats with suberoylanilide hydroxamic acid. / McDonnel, Samantha J.; Liepnieks, Molly L.; Murphy, Brian G.

In: Antiviral Research, Vol. 108, No. 1, 2014, p. 74-78.

Research output: Contribution to journalArticle

McDonnel, Samantha J. ; Liepnieks, Molly L. ; Murphy, Brian G. / Treatment of chronically FIV-infected cats with suberoylanilide hydroxamic acid. In: Antiviral Research. 2014 ; Vol. 108, No. 1. pp. 74-78.
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abstract = "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 na{\"i}ve 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 h 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.",
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