Nucleosides for the treatment of respiratory RNA virus infections

Jordan, Paul C; Stevens, Sarah K; Deval, Jerome

Influenza virus is a (-)ssRNA virus and a member of the Orthomyxoviridae family. 5 There are four influenza genera within this family, called A, B, C, or D. Influenza A and B contain hemagglutinin and neuraminidase envelope glycoproteins. Influenza C and D have a single surface glycoprotein called the hemagglutinin-esterase fusion protein. 6, 7 Antigenic variation in these glycoproteins results in limited vaccine protection. Influenza, or the flu, presents with symptoms such as headache, cough, fever, sore throat, malaise, and chills. 8 Generally, the flu lasts from 5 days to 2 weeks and the severity of infection is determined by the host. The highest incidence of influenza infection occurs in younger patients (<25 years old) where a shorter infection is typical, while those at risk for longer and more severe illness and complications associated with infection are the pediatric (<2 years old) and geriatric populations (>65 years old), pregnant women, and immunocompromised individuals. 9, 10 It is estimated that 3-5 million cases of the flu occur annually around the globe, with a quarter to half million deaths resulting from these illnesses. 11 PIV (Paramyxoviridae family), RSV, and HMPV (Pneumoviridae family) Until recently, PIV, HMPV, and RSV were all categorized in the Paramyxoviridae family due to their phylogenetic proximity in the order Mononegavirales, the non-segmented negative-strand RNA viruses. More recently, RSV and HMPV have been assigned as members of the newly formed Pneumoviridae family. 12 While influenza outbreaks are most prevalent in the winter, some viruses such as PIV persist year-round. Human PIV has four types (1 to 4) and was known historically to induce respiratory complications mainly in children and the immunocompromised; however, more recently, it has been identified as a concern in the adult population as well. 13 Symptoms of PIV include upper and lower respiratory tract infection, middle ear inflammation, bronchitis, pneumonia, and croup, the last of which results in the most hospitalizations in the pediatric patients infected by this virus. 14, 15 Up to one-third of the nearly 5 million annual cases of lower respiratory tract infection in children is at least partially due to the presence of PIVs. 16 RSV and PIV infections are among the most common reason for hospitalization of young children. 17, 18 The two strains of RSV, A and B, are distinguished by genetic variations in the G surface glycoprotein. 19 Dissimilar to PIV, RSV occurs mostly in the winter months in its target pediatric population. Symptoms include runny nose, nasal inflammation, cough, sore throat, low-grade fever, wheezing, bronchiolitis, and pneumonia. 20 Current estimates in developing and industrialized countries suggest as many as 33 million cases of RSV worldwide in the pediatric population less than 5 years old, 10% of which require hospitalization, and 2% to 18% of hospitalized cases result in mortality. This amounts to between 66,000 and 600,000 deaths in young children annually. 18, 21 HMPV, like RSV and influenza, tends to have greatest prevalence in the winter and studies have shown that by the age of 5 years, nearly all children have been infected with this virus. 22 The clinical manifestations of infection with this virus are upper and lower respiratory tract infections, bronchiolitis, middle ear inflammation, fever, chills, pneumonitis, and wheezing. 23 Of note, HMPV tends to occur in populations with seasonal inconsistency