Favipiravir is an oral broad-spectrum inhibitor of viral RNA-dependent RNA polymerase that is approved for treatment of influenza in Japan. We conducted a prospective, randomized, open-label, multicenter trial of favipiravir for the treatment of COVID-19 at 25 hospitals across Japan. Eligible patients were adolescents and adults admitted with COVID-19 who were asymptomatic or mildly ill and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned at a 1:1 ratio to early or late favipiravir therapy (the same regimen starting on day 6 instead of day 1). The primary endpoint was viral clearance by day 6. The secondary endpoint was change in viral load by day 6. Exploratory endpoints included time to defervescence and resolution of symptoms. Eighty-nine patients were enrolled, of whom 69 were virologically evaluable. Viral clearance occurred within 6 days in 66.7% and 56.1% of the early and late treatment groups (adjusted hazard ratio [aHR], 1.42; 95% confidence interval [95% CI], 0.76–2.62). Of 30 patients who had a fever (≥37.5°C) on day 1, time to defervescence was 2.1 days and 3.2 days in the early and late treatment groups (aHR, 1.88; 95%CI, 0.81–4.35). During therapy, 84.1% developed transient hyperuricemia. Favipiravir did not significantly improve viral clearance as measured by RT-PCR by day 6 but was associated with numerical reduction in time to defervescence. Neither disease progression nor death occurred to any of the patients in either treatment group during the 28-day participation (Japan Registry of Clinical Trials jRCTs041190120).

Human herpesvirus 6 (HHV-6) is a T-cell-tropic betaherpesvirus. A glycoprotein (g) complex that is unique to HHV-6, gH/gL/gQ1/gQ2, is a viral ligand for its cellular receptor, human CD46. However, whether complex formation or one component of the complex is required for CD46 binding and how the complex is transported in cells are open questions. Furthermore, in HHV-6-infected cells the gQ1 protein modified with N-linked glycans is expressed in two forms with different molecular masses: an 80-kDa form (gQ1-80K) and a 74-kDa form (gQ1-74K). Only gQ1-80K, but not gQ1-74K, forms the complex with gQ2, gH, and gL, and this four-component complex is incorporated into mature virions. Here, we characterized the molecular context leading to the maturation of gQ1 by expressing combinations of the individual gH/gL/gQ1/gQ2 components in 293T cells. Surprisingly, only when all four molecules were expressed was a substantial amount of gQ1-80K detected, indicating that all three of the other molecules (gQ2, gH, and gL) were necessary and sufficient for gQ1 maturation. We also found that only the tetrameric complex, and not its subsets, binds to CD46. Finally, a gQ2-null virus constructed in the BAC (bacterial artificial chromosome) system could not be reconstituted, indicating that gQ2 is essential for virus growth. These results show that gH, gL, gQ1, and gQ2 are all essential for the trafficking and proper folding of the gH/gL/gQ1/gQ2 complex and, thus, for HHV-6 infection.

Human herpesvirus 6 (HHV-6) is a T cell-tropic betaherpesvirus. HHV-6 can be classified into two variants, HHV-6A and HHV-6B, based on differences in their genetic, antigenic, and growth characteristics and cell tropisms. The function of HHV-6B should be analyzed more in its life cycle, as more than 90% of people have the antibodies for HHV-6B but not HHV-6A. It has been shown that the cellular receptor for HHV-6A is human CD46 and that the viral ligand for CD46 is the envelope glycoprotein complex gH/gL/gQ1/gQ2; however, the receptor-ligand pair used by HHV-6B is still unknown. In this study, to identify the glycoprotein(s) important for HHV-6B entry, we generated monoclonal antibodies (MAbs) that inhibit infection by HHV-6B. Most of these MAbs were found to recognize gQ1, indicating that HHV-6B gQ1 is critical for virus entry. Interestingly, the recognition of gQ1 by the neutralizing MAb was enhanced by coexpression with gQ2. Moreover, gQ1 deletion or point mutants that are not recognized by the MAb could nonetheless associate with gQ2, indicating that although the MAb recognized the conformational epitope of gQ1 exposed by the gQ2 interaction, this epitope was not related to the gQ2 binding domain. Our study shows that HHV-6B gQ1 is likely a ligand for the HHV-6B receptor, and the recognition site for this MAb will be a promising target for antiviral agents.Human herpesvirus 6 (HHV-6) was first isolated from patients with lymphocytic disorders in1986 (36) and was subsequently shown to be the causative agent of exanthem subitum (ES) (48). Currently, HHV-6 can be classified into two variants, HHV-6A and HHV-6B, based on differences in genetic, antigenic, and growth characteristics and cell tropisms (1,5,7,8). HHV-6B causes infant ES, and more than 90% of people have antibodies (Abs) against HHV-6B (31, 38), while the pathogenesis of HHV-6A is still unknown. Recently, it was shown that a reactivation of HHV-6B causes encephalitis in immunocompromised hosts (13,45,46) and possibly enhances the severity of drug-induced sensitivity syndrome (14).Human CD46, a regulator of the complement activation receptor expressed on all nuclear cells, is a receptor for HHV-6 (37), and its viral ligand is the envelope glycoprotein complex gH/gL/gQ1/gQ2 (3, 28). Although this complex can bind CD46 (28), those of some clinical isolates, including laboratory strains of HHV-6B, do not bind it (24, 26). The gQ gene is unique because it is conserved only among HHV-6A, HHV-6B, and 15,19). Recently, we successfully reconstituted a virus from the HHV-6 genome (43) and found that HHV-6 gQ1 is essential for virus growth and probably for entry.As monoclonal antibodies (MAbs) against gH and gB inhibit virus-induced cell fusion and infection, gH and gB are thought to be fusogenic candidates (39). In addition, as it is common to herpesviruses generally, gH homologues expressed on viral envelopes form a complex with gL homologues (18,20,21).In addition to gH/gL/gQ1/gQ2, another gH/gL complex, gH/ gL/gO, is present in the viral envelopes of both ...