Determination of Ebola Virus Mutation Frequency
The speed of molecular evolution is linked to virus mutation frequency. Using a recombinant Ebola virus (EBOV) carrying the GFP gene along with deep-sequencing analysis, Alfson et al. (p. 2345–2355) determined that the mutation frequency for EBOV without negative selection is 4.1 × 10–4 mutations per nucleotide sequenced. This frequency is similar to that of other RNA viruses and suggests a high potential for adaptation. Other viruses exhibit dramatically reduced fitness associated with minor changes in mutation frequency. For EBOV, the mutagenic drug ribavirin increased mutation frequency 27-fold and reduced infectivity. In animals, ribavirin improved outcome following infection with lethal doses of EBOV. These findings illustrate the potential therapeutic value of modifying EBOV mutation frequency.
Effect of ribavirin on EBOV infectivity in culture.
Inhibition of ATM-Driven p53 Activity by Two Gammaherpesvirus Proteins
DNA damage responses (DDRs) are triggered by gammaherpesvirus lytic replication. Whether DDR induction has consequences for virus replication is not known. Studying murine gammaherpesvirus 68 (MHV68), Sifford et al. (p. 2571–2585) demonstrate that tumor suppressor p53 is activated downstream of DDR kinase ataxia telangiectasia mutated (ATM) during MHV68 infection. However, MHV68 homologs of the latency-associated nuclear antigen (LANA) and shutoff and exonuclease protein (SOX) enforce dominant inhibition of p53 responses in infected cells. These findings highlight viral mechanisms for overcoming potentially detrimental outcomes of DDR induction during viral replication.
p53 induction by doxorubicin treatment is suppressed during MHV68 lytic replication.
Human MicroRNA miR-532 Restricts West Nile Virus Replication
Host responses to West Nile virus infection are primarily associated with innate and adaptive immunity. However, there may be a role for host microRNAs in this process. Slonchak et al. (p. 2388–2402) identified human microRNA miR-532 as an antiviral microRNA and showed that it restricts West Nile virus infection by diminishing expression of host genes SESTD1 and TAB3, which are required for viral replication. These results highlight the importance of host microRNAs in controlling RNA virus infections in mammals.
miR-532 inhibits West Nile virus replication in human cells.
A Distinct Prosurvival Mechanism in Cytomegalovirus-Infected Carrier Monocytes
Human cytomegalovirus (HCMV) infects short-lived circulating blood monocytes and uses these cells to disseminate and establish viral persistence. Collins-McMillen et al. (p. 2356–2371) report a viral survival mechanism whereby HCMV usurps the cellular antiapoptotic signaling pathways of infected cells to extend their limited lifespan and combat the antiviral proapoptotic response to infection. These findings highlight the evolution of HCMV in association with cells of the myeloid lineage, as the virus effectively reprograms infected cells in the absence of viral gene expression to promote an outcome that favors viral persistence.
Cooperative signaling through EGFR and cellular integrins promotes survival of infected monocytes at multiple apoptotic checkpoints.
Harnessing Host Innate Immunity for Broad-Spectrum Antiviral Therapy
RIG-I-like receptors (RLRs) are cytoplasmic pathogen recognition receptors that are essential for control of RNA virus infection. Pattabhi et al. (p. 2372–2387) identified drug-like compounds that activate RLR-dependent innate immune responses to control infection by RNA viruses of diverse genera, including Arenaviridae (Lassa virus), Filoviridae (Ebola virus), Flaviviridae (dengue virus, hepatitis C virus, and West Nile virus), Orthomyxoviridae (influenza A virus), and Paramyxoviridae (Nipah virus and respiratory syncytial virus). This work points the way forward in the design of small molecule therapeutics to induce and enhance host innate antiviral immunity for protection against contemporary and emerging RNA viruses.
Broad-spectrum antiviral effect of KIN1400 analogs.