Catch a virus by the tail

Study uncovers a key mechanism that allows some of the world’s deadliest viruses to replicate.

Some RNA viruses such as Segmented negative-sense (SNS) RNA viruses initiate infection by delivering into cells a suite of genomic RNA segments, each sheathed by the viral nucleocapsid protein and bound by the RNA-dependent RNA-polymerase (RdRP).

Such segmented RNA viruses, including a few that cause human diseases like influenza, have long been a puzzle to scientists: How do they accomplish the precise copying and insertion of each segment? How do they ensure that individual segments are all copied by the same enzyme and that each segment can make different amounts of RNA?

Harvard scientists seem to found a surprising answer: the viral machinery in charge of this survival-ensuring maneuver becomes activated by RNA from the tail end of the segment, opposite to where the copying starts.

According to scientists, the study could potentially target to inhibit the replication of segmented viruses including several emerging and highly fatal viruses such as Lassa fever virus, bunyaviruses like La Crosse and Rift Valley fever, as well as the better-known and more common influenza viruses.

Sean P.J. Whelan, professor of microbiology at HMS and director of the Harvard Program in Virology said, “Climate change has altered and intensified the spread of some serious and emerging viruses to new geographic regions, creating an acute challenge to global health. Our findings identify a critical mechanism that allows some of these pathogens to replicate and survive.”

“Being infected with the Lassa fever virus, for example, is rarely fatal, but once the actual disease develops, it can cause hemorrhaging in multiple organs in one out of five people. The mortality rate can reach 50 percent during epidemics.”

During the study, scientists worked with the Machupo virus, an arenavirus that, like Lassa virus, infects rodents, which transmit the virus to humans, in whom it can cause fatal hemorrhagic fevers.

Machupo virus has only two segments — called small and large segments — offering a much simpler way to understand how segments are copied in the correct amounts.

Previous clues about this mechanism came from research on influenza and La Crosse viruses that showed the viral protein responsible for copying the key segment — RNA-dependent RNA-polymerase (RdRP) — interacted with the 5′ end of the segment, which is the exact opposite end to the location where the protein initiates copying. Yet, the importance of this interaction was not fully understood.

Scientists found that mixing short 13-nucleotide RNAs from the 5′ end of the Machupo virus segments with the RdRP, the catalyst that initiates RNA replication, stimulated the ability of this enzyme to copy the viral segment. The two-segment Machupo virus contains four subtly different 5′ RNAs that each bind the RdRP enzyme.

Most importantly, scientists noted that those RNAs dictate which of four different start sites the enzyme actually uses.

The outcomes do not only highlight an important question in basic virology but also identify a target that may illuminate how to develop a new class of antiviral drugs directed at this essential 5′ RNA activation.

The study is published in the journal PNAS.

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