Study reveals key mechanism allowing some of the deadliest viruses in the world to replicate

Viruses are master invaders. They cannibalize host cells by injecting their genetic material, often making thousands of copies in a single cell for replication and survival.

Some RNA viruses insert their genetic material in one piece, while others cut it into pieces. These are well-named segmented viruses.

Segmented RNA viruses, many of which cause human diseases such as influenza, have long been an enigma for researchers: how do they achieve accurate copy and insertion of each segment? How do they ensure that individual segments are all copied by the same enzyme while ensuring that each segment can produce different amounts of RNA? Such exquisite regulation is essential to make the correct levels of viral proteins necessary for successful replication.

Research conducted by scientists at the Blavatnik Institute of Medicine at Harvard Medical School provides a surprising answer: the viral machinery responsible for this survival-enhancing maneuver is activated by RNA from the end opposite of the segment where the copy begins.

The results, published on May 9 in PNASidentify new potential targets for inhibiting segmented virus replication. This group includes several very deadly emerging viruses, such as Lassa fever virus, Bunyavirus like La Crosse and Rift Valley Fever, as well as the better known and more common influenza viruses.

"Climate change has altered and intensified the spread of serious and emerging viruses in new geographic regions, creating a major challenge to global health, and our results provide a critical mechanism for some of these pathogens to replicate and survive. "said Sean PJ Whelan. , Professor of Microbiology at HMS and Director of the Harvard Virology Program.

Infections with Lassa fever, for example, are rarely fatal, but once the disease has appeared, it can cause haemorrhages, or bleeding, in several organs in one in five people. According to the Centers for Disease Control and Prevention, the mortality rate can reach 50% during epidemics.

In the study, Whelan and his co-author, Jesse Pyle, a graduate student from Whelan's lab, worked with the Machupo virus, an arenavirus, which, like the Lassa virus, infects rodents, which in turn , transmit the virus to the man where it causes fatal haemorrhagic fevers.

Unlike the influenza virus, whose genome has eight segments, the Machupo virus has only two segments, called small and large segments, offering a much simpler way to understand how different segments are copied in the correct amounts.

Previous research on influenza and lacrosse viruses has revealed clues about the presence of the viral protein responsible for copy of the key segment – RNA-dependent RNA polymerase (RdRP) – interacting with the 5 "end of the segment, which corresponds opposite end to the location where the protein begins to copy. However, the importance of this interaction has not been fully understood.

The experiments revealed that mixing short 13-nucleotide RNAs from the 5-end segments of the Machupo virus with the RdRP, the catalyst that initiates RNA replication, has has boosted the ability of this enzyme to copy the viral segment. The two-segment Machupo virus contains four slightly different 5 RNAs that each bind to the RdRP enzyme. Remarkably, scientists have observed that these RNAs dictate which of the four different starting sites the enzyme actually uses.

Whelan and Pyle state that these findings not only shed light on an important issue of virology, but also identify a new target that could inform how to develop a new class of antiviral drugs targeting this essential RNA activation. # 39 ;.

Most antiviral drugs currently on the market directly target viral enzymes involved in the replication of genetic material or in the treatment of viral proteins. None, however, interferes with the particular mechanism described in this study.

"Our work demonstrates that 5 'RNA and its binding site on the viral enzyme are potential new targets for the inhibition of viral replication," Whelan said. "An important next goal would be to look for molecules that interfere with this process and set the stage for the design of new drugs."