Drug Sensitivity of Vaccine-Derived Rubella Viruses and Quasispecies Evolution in Granulomatous Lesions of Two Ataxia-Telangiectasia Patients Treated with Nitazoxanide

Abstract

A strong association between rubella virus (RuV) and chronic granulomas, in individuals with inborn errors of immunity, has been recently established. Both the RA27/3 vaccine and wild-type RuV strains were highly sensitive to a broad-spectrum antiviral drug, nitazoxanide (NTZ), in vitro. However, NTZ treatment, used as a salvage therapy, resulted in little or no improvements of RuV-associated cutaneous granulomas in patients. Here, we report investigations of possible causes of treatment failures in two ataxia-telangiectasia patients. Although a reduction in RuV RNA in skin lesions was detected by real-time RT-PCR, live immunodeficiency-related vaccine-derived rubella viruses (iVDRV) were recovered from granulomas, before and after the treatments. Tizoxanide, an active NTZ metabolite, inhibited replications of all iVDRVs in cultured A549 cells, but the 50% and 90% inhibitory concentrations were 10–40 times higher than those for the RA27/3 strain. There were no substantial differences in iVDRV sensitivities, neither before nor after treatments. Analysis of quasispecies in the E1 gene, a suspected NTZ target, showed no effect of NTZ treatments on quasispecies’ complexity in lesions. Thus, failures of NTZ therapies were likely due to low sensitivities of iVDRVs to the drug, and not related to the emergence of resistance, following long-term NTZ treatments.

Rubella virus‐associated necrotizing neutrophilic granuloma in a patient with common variable immunodeficiency

“…Our patient's RuV‐associated cutaneous granulomas responded though not completely to high‐potency topical steroids under occlusion. Other reported therapies include the broad‐spectrum antiviral drug nitazoxanide, 11,12 TNF‐alpha and IL‐1R inhibitors, 8 and ribavirin 13 with varying success. Hematopoietic stem cell transplant has been the most effective reported treatment modality with resolution of RuV‐associated granulomas in several patients 8,14 .…”

Rubella Virus-Associated Cutaneous Granulomas in an Adult With TAP1 Deficiency Case Report

“…Interestingly, the RuV sequences found in these patients exhibited variation from currently circulating strains but shared striking similarity with the Wistar 27/3 vaccine strain. Subsequent evidence for RuV genomic RNA within the nasopharyngeal cavities of patients diagnosed with PIDs strongly indicated the ongoing replication and evolution of the rubella vaccine in those individuals [2][3][4][5][6][7][8] .…”

Rubella virus chronic inflammatory disease and other unusual viral phenotypes in inborn errors of immunity

“…Treatment outcomes have been disappointing. Nitazoxanide and ribavirin have activity against RuV and iVDRV in vitro but use in humans has demonstrated modest efficacy 97–99 . The best outcomes have been with hematopoietic cell transplantation although not all patients are candidates for this intervention 97 .…”

“…Nitazoxanide and ribavirin have activity against RuV and iVDRV in vitro but use in humans has demonstrated modest efficacy. [97][98][99] The best outcomes have been with hematopoietic cell transplantation although not all patients are candidates for this intervention. 97 A recent report of nucleoside analogs with anti-rubella activity suggests direct virustargeting treatment could be possible.…”