Treatment of norovirus infections: Moving antivirals from the bench to the bedside

Abstract

Noroviruses (NV) are the most common cause of acute gastrointestinal illness in the United States and worldwide. The development of specific antiviral countermeasures has lagged behind that of other viral pathogens, primarily because norovirus disease has been perceived as brief and self-limiting and robust assays suitable for drug discovery have been lacking. The increasing recognition that NV illness can be life-threatening, especially in immunocompromised patients who often require prolonged hospitalization and intensive supportive care, has stimulated new research to develop an effective antiviral therapy. Here, we propose a path forward for evaluating drug therapy in norovirus-infected immunocompromised individuals, a population at high risk for serious and prolonged illness. The clinical and laboratory features of norovirus illness in immunocompromised patients are reviewed, and potential markers of drug efficacy are defined. We discuss the potential design of clinical trials in these patients and how an anti-viral therapy that proves effective in immunocompromised patients might also be used in the setting of acute outbreaks, especially in confined settings such as nursing homes, to block the spread of infection and reduce the severity of illness. We conclude by reviewing the current status of approved and experimental compounds that might be evaluated in a hospital setting.

Advances in Norovirus Biology

“…For detailed descriptions of antiviral approaches for controlling NoVs, the reader is referred to other recent reviews (Arias et al, 2013; Kaufman et al, 2014). …”

“…Since many structural features are conserved across the NoV family, this approach has the potential to yield inhibitors effective against the wide diversity of NoV strains. To date, a multitude of candidate inhibitors, targeting primarily the viral Pro, RdRp, and VP1, have been tested in recombinant protein or cell-based assays, with activities typically in the low micromolar range (Arias et al, 2013; Kaufman et al, 2014). The only drug candidate tested in vivo so far is the nucleoside analog 2′-C-methylcytidine (2CMC) (Rocha-Pereira et al, 2013).…”

Norovirus Cell Tropism Is Determined by Combinatorial Action of a Viral Non-structural Protein and Host Cytokine

“…During the acute phase of infection, HNoV causes vomiting and diarrhea, which typically resolves within one to two days (Atmar et al, 2008; Rockx et al, 2002). Viral shedding into the stool, however, can continue for weeks to months in asymptomatic patients (Gustavsson et al, 2017; Kaufman et al, 2014; Saito et al, 2013; Teunis et al, 2015), and for years in immunocompromised patients (Bok and Green, 2012). This phenomenon is referred to as persistence herein.…”

Sequential Gastroenteritis Outbreaks in a Single Year Caused by Norovirus Genotypes GII.2 and GII.6 in an Institutional Setting

“…Norovirus is a leading cause of acute nonbacterial gastroenteritis [1, 2]. The positive-sense norovirus RNA genome is organized into 3 open reading frames (ORFs).…”