Researchers at the Ohio State University report they have settled a matter of scientific debate. In a new study, the researchers discovered a chemical modification in the HIV-1 RNA genome that is now confirmed to be key to the virus’s ability to survive and thrive after infecting host cells.

Their findings are published in Nature Microbiology in an article titled, “Single-molecule epitranscriptomic analysis of full-length HIV-1 RNAs reveals functional roles of site-specific m6As.”

“Although the significance of chemical modifications on RNA is acknowledged, the evolutionary benefits and specific roles in human immunodeficiency virus (HIV-1) replication remain elusive,” the researchers wrote. “Most studies have provided only population-averaged values of modifications for fragmented RNAs at low resolution and have relied on indirect analyses of phenotypic effects by perturbing host effectors. Here we analyzed chemical modifications on HIV-1 RNAs at the full-length, single RNA level, and nucleotide resolution using direct RNA sequencing methods.”

This change to HIV-1 RNA, a tiny chemical modification on the adenosine building block of RNA known as m6A, is a common RNA editing process in all life forms that involves altering gene expression and protein production. The functional effect often represents a cellular solution but, in some cases, leads to disease.

By developing technological advances to observe a full length of HIV-1 RNA, the Ohio State University researchers discovered that m6A modification occurs nearly exclusively at three specific locations on the HIV-1 RNA genome and these three m6As are crucial in viral replication.

“These sites are very important for producing virus proteins and for producing viral genomic RNA,” said senior study author Sanggu Kim, PhD, associate professor of veterinary biosciences and an investigator in the Center for Retrovirus Research at the Ohio State University.

“An intriguing question is, why does HIV maintain multiple m6As? Our conclusion is that m6A is so important that HIV wants to have multiples to have redundancy. If it loses one or two, it’s OK. If it loses all three, it’s a problem.”

Further work with drug development will take time. However, Kim said the finding suggests targeting the site-specific m6A modifications could be the basis of designing an important new treatment for HIV infection.

“We know every aspect of RNA function is very important, but we don’t really know how exactly these chemical and structural modifications of RNAs regulate virus infection,” Kim said.

Though the m6A (short for N6-methyladenosine) modification was known to exist in HIV-1, previous studies had produced conflicting results about whether it helped or harmed the virus.

Kim and colleagues used nanopore direct RNA sequencing to view the full length of HIV-1’s RNA genome.

The team first discovered the three m6A modifications and their specific locations. From there, the researchers analyzed individual RNA molecules with distinct ensembles of m6A modifications, including those with multiple m6As and those with just one of the three m6As.

“Until now we didn’t know which exact nucleotides are modified and how they function, and how it’s important for viruses or how it’s important for cells. Our paper addresses the keys to these important questions,” Kim explained.

“Why would HIV need all three modifications if they’re functioning in the same way?” he said. “Our study is the first to show that HIV-1 utilizes this unique, important mechanism at the RNA level for its evolutionary benefit.”

Almost all existing HIV drugs block virus replication, but no medications inhibit viral RNA and protein production. There is more to learn about the RNA modification in HIV-1, but Kim said the work hints at the potential to develop therapies that could target these later steps.

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