Emerging Roles of N6-Methyladenosine on HIV-1 RNA Metabolism and Viral Replication

Abstract

N6-methyladenosine (m6A) is the most abundant internal modification present in Eukaryotic mRNA. The functions of this chemical modification are mediated by m6A-binding proteins (m6A readers) and regulated by methyltransferases (m6A writers) and demethylases (m6A erasers), which together are proposed to be responsible of a new layer of post-transcriptional control of gene expression. Despite the presence of m6A in a retroviral genome was reported more than 40 years ago, the recent development of sequencing-based technologies allowing the mapping of m6A in a transcriptome-wide manner made it possible to identify the topology and dynamics of m6A during replication of HIV-1 as well as other viruses. As such, three independent groups recently reported the presence of m6A along the HIV-1 genomic RNA (gRNA) and described the impact of cellular m6A writers, erasers and readers on different steps of viral RNA metabolism and replication. Interestingly, while two groups reported a positive role of m6A at different steps of viral gene expression it was also proposed that the presence of m6A within the gRNA reduces viral infectivity by inducing the early degradation of the incoming viral genome. This review summarizes the recent advances in this emerging field and discusses the relevance of m6A during HIV-1 replication.

Colocalization of m6A and G-Quadruplex-Forming Sequences in Viral RNA (HIV, Zika, Hepatitis B, and SV40) Suggests Topological Control of Adenosine N6-Methylation

“…104−106 Among the data differing observations and interpretations exist; these have been recently reviewed. 107−109 For the present discussion, key points include overlap of m 6 A sites in the 3′-UTR of the HIV-1 RNA genome in which there are conserved PQSs shown to adopt G4 folds. 38 The sequencing approaches applied to identify m 6 A were low- and high-resolution m 6 A sequencing.…”

An epitranscriptomic switch at the 5′-UTR controls genome selection during HIV-1 genomic RNA packaging

“…6). This differential epitranscriptomic regulation exerted on the full-length RNA depending on its functions (mRNA or gRNA) may also help to explain the controversies reported in the literature 29 . As such, while the presence of m 6 A favors Gag synthesis through YTHDF proteins acting on the full-length RNA molecules destined to serve as mRNA 21 , the same cytoplasmic m 6 A readers may recognize specific features and drive degradation of the incoming viral RNA early upon infection (i.e., when the full-length RNA acts as gRNA) 22 .…”

It’s the Little Things (in Viral RNA)

“…1B ). On the other hand, based on experiments demonstrating a significant decrease in viral replication upon METTL3 and METTL14 inhibition, along with an increase in viral replication upon AlkBH5 depletion, it seems that m 6 A plays an important role in the regulation of the HIV life cycle ( 25 ). This effect may be caused by the HIV-1 Rev protein preferentially binding to a Rev response element (RRE) containing the m 6 A modification and promoting nuclear export of the viral mRNA to the cytosol ( Fig.…”

“…The differences in results from studies of m 6 A in HIV can be attributed to several factors, such as the cell type used, the phase of the viral life cycle, the method used to detect m 6 A, etc. These discrepancies are thoroughly discussed in a review focusing specifically on m 6 A ( 25 ). It is also important to note that the viral infection can change the abundance of m 6 A in cellular RNA ( 51 ).…”