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 antiviral 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.

Keywords: Antiviral; Diarrhea; Drug treatment; Immunocompromised; Norovirus; Transplant.

Fig. 1

See (Green, 2013) for a review. The norovirus positive-sense RNA genome is approximately 7700 nucleotides in length, polyadenylated, and organized into three open reading frames (ORFs). ORF1 encodes three obligatory enzymes (NTPase, pro, pol) involved in virus replication that might serve as targets for antiviral drugs. The other three ORF1-encoded non-structural proteins are also essential for replication. VPg, which is covalently attached to the 5′ end of the viral genome, interact with host cell proteins, especially translation initiation factors, and the remaining two proteins interact with host factors and membranes. Interruption of such virus-host interactions may offer additional potential drug targets. The major structural protein of the virus, VP1, is encoded by ORF2 and the minor structural protein, VP2 is encoded by ORF3. Compounds that block viral entry into cells or inhibit virus assembly might prove effective. Both structural proteins are translated separately from a single sub-genomic messenger RNA. ORF1 is translated as a single polyprotein directly from the poly-adenylated genomic RNA, and is cleaved into individual non-structural proteins by the viral protease. ORF2 is depicted as offset to denote short overlaps with both ORF1 and ORF3.