Treatment of chronically FIV-infected cats with suberoylanilide hydroxamic acid

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 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.

Viral Reservoirs in Lymph Nodes of FIV-Infected Progressor and Long-Term Non-Progressor Cats during the Asymptomatic Phase

“…During this study period, plasma vRNA was not detected within the limits of the real-time PCR assay for any of the FIV-infected and uninfected cats, consistent with our previous observations [ 10 , 11 , 18 ]. Proviral DNA loads for unfractionated PBMCs and PLN-derived leukocytes, as well as from blood and PLN enriched CD4+ and CD21+ populations were determined by real-time PCR.…”

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

“…This report also revealed that latent infection was characterized by the association of the FIV 5¢ long terminal repeat (LTR) promoter with host histone proteins that were hypermethylated and deacetylated, consistent with a condensed chromatin state [123]. Subsequent reports demonstrated that latently FIV-infected cells could be reactivated ex vivo through the administration of histone deacetylase inhibitors suberoylanilide hydroxamic acid, valproic acid, trichostatin A, and sodium butyrate (NaB) and a histone methyltransferase inhibitor 3-deazanoplanocin A [124,125]. Similar findings were reported in two studies by Tadafumi and Chan who used histone deacytelase NaB and protein kinase-C inhibitors, respectively, to reverse FIV latency [120,126].…”

Multi-dose Romidepsin Reactivates Replication Competent SIV in Post-antiretroviral Rhesus Macaque Controllers

“…Though logical, experience to date has not fulfilled these expectations. Specifically, studies have demonstrated that: only a small fraction of proviruses present in resting CD4 + T cells are reactivated by a single round of HDACi treatment in vitro [ 53 ]; reactivation of infected, resting CD4 + T cells by vorinostat did not result in viral CPE-mediated cell death [ 42 ]; impairment of host HIV-specific CTLs’ functions is specifically associated with immunodeficiency characteristic to HIV infection even in treated patients [ 54 ]; viral clearance by the CTLs only occurs in elite controllers [ 55 ]; the effect of various LRAs on latently infected cells, both in vivo and ex vivo , is highly variable [ 45 , 56 , 57 ]; in vitro treatment of cells with HDACi can impair CTL function [ 51 ]; and, finally, much of the virus present in latently infected cells in individuals that started ART in the chronic phase of infection contains escape mutations for immunodominant epitopes [ 58 ].…”