Inhibition of rubella virus replication by the broad-spectrum drug nitazoxanide in cell culture and in a patient with a primary immune deficiency

Abstract

Persistent rubella virus (RV) infection has been associated with various pathologies such as congenital rubella syndrome, Fuchs's uveitis, and cutaneous granulomas in patients with primary immune deficiencies (PID). Currently there are no drugs to treat RV infections. Nitazoxanide (NTZ) is an FDA-approved drug for parasitic infections, and has been recently shown to have broad-spectrum antiviral activities. Here we found that empiric 2-month therapy with oral NTZ was associated in the decline/elimination of RV antigen from lesions in a PID patient with RV positive granulomas, while peginterferon treatment had no effect. In addition, we characterized the effects of NTZ on cell culture models of persistent RV infection. NTZ significantly inhibited RV replication in a primary culture of human umbilical vein endothelial cells (HUVEC) and Vero and A549 epithelial cell lines in a dose dependent manner with an average 50% inhibitory concentration of 0.35 μg/ml (1.1 μM). RV strains representing currently circulating genotypes were inhibited to a similar extent. NTZ affected early and late stages of infection by inhibiting synthesis of cellular and RV RNA and interfering with intracellular trafficking of the RV surface glycoproteins, E1 and E2. These results suggest a potential application of NTZ for the treatment of persistent rubella infections, but more studies are required.

Rubella Virus-Associated Cutaneous Granulomatous Disease: a Unique Complication in Immune-Deficient Patients, Not Limited to DNA Repair Disorders

“…Consideration should be given to use of curative treatment with hematopoietic stem cell transplantation using modified reduced intensity conditioning in selected patients with DNA repair disorders [8]. Other areas of active exploration include the use of agents such as nitazoxanide that may possess broad antiviral properties [9]. Interestingly, the responses reported postconditioning among several of the NBS patients, one AT patient, one DNA ligase 4-deficient patient, and one Artemis-deficient patient suggests that the elimination of rubella virus-specific (functionally impaired) effector T cells may have resulted in the disappearance of the cutaneous granulomatous disease.…”

Nitazoxanide May Modify the Course of Progressive Multifocal Leukoencephalopathy

“…The CD4/CD8 ratio was reduced at 0.88 15 months prior to PML diagnosis, but restored to a value of 3.5 five weeks after the start of nitazoxanide, indicating CD4 + T cell expansion. No obvious improvement in her chronic wounds was observed although the RV was eliminated from the lesions during nitazoxanide treatment [3].…”

“…On day −66, experimental peginterferon-alfa-2a treatment (Pegasys®) against RV was started with a weekly dose of 180 μg for three weeks followed by a dose reduction due to dizziness associated with the injection. A seven-week treatment failed to improve the condition of her skin lesions [3].…”

“…However, our clinical experience described in this case report supports the possibility that nitazoxanide, a broad-spectrum antiparasitic and antiviral drug [2], may have helped in controlling the JCV in a single patient with PML associated with combined PID. This antiviral effect of nitazoxanide may have been produced by induction of innate immunity, downregulation of viral receptors, or interference with maturation of viral proteins [2,3].…”

“…Based on its known broad antiviral activity [2], she started receiving oral nitazoxanide 500 mg (Alinia®) twice daily on day +3 with an attempt to treat both PML and RV. A single 500mg oral dose of nitazoxanide has been reported to produce a peak plasma concentration of 10 μg/ml in human, while the IC50 has been between 0.2 to 1.5 μg/ml for rubella, influenza, coronavirus, and hepatitis C [2,3]. On day +45 (acute), ex vivo interferon gamma (IFNγ) and tumor necrosis factor alpha (TNFα) secretion by CD4 + and CD8 + T cells upon JCV VP1 peptide stimulation were normal compared to two natalizumab-associated (Fig.…”