Functional Impacts of Epitranscriptomic m6A Modification on HIV-1 Infection

Abstract

Epitranscriptomic RNA modifications play a crucial role in the posttranscriptional regulation of gene expression. N6-methyladenosine (m6A) is the most prevalent internal modification of eukaryotic RNA and plays a pivotal role in RNA fate. RNA m6A modification is regulated by a group of cellular proteins, methyltransferases (writers) and demethylases (erasers), which add and remove the methyl group from adenosine, respectively. m6A modification is recognized by a group of cellular RNA-binding proteins (readers) that specifically bind to m6A-modified RNA, mediating effects on RNA stability, splicing, transport, and translation. The functional significance of m6A modification of viral and cellular RNA is an active area of virology research. In this review, we summarize and analyze the current literature on m6A modification of HIV-1 RNA, the multifaceted functions of m6A in regulating HIV-1 replication, and the role of viral RNA m6A modification in evading innate immune responses to infection. Furthermore, we briefly discuss the future directions and therapeutic implications of mechanistic studies of HIV-1 epitranscriptomic modifications.

Single-molecule epitranscriptomic analysis of full-length HIV-1 RNAs reveals functional roles of site-specific m6As

“…The functions of m 6 A modifications are determined by host effectors that catalyse, recognize and remove such modifications (known as writers, readers and erasers, respectively) 3 , 43 . Mounting evidence also suggest that these modifications have site-specific and context-dependent roles, controlling local RNA–protein interactions by modulating the RNA structures where the interactions occur 15 – 19 .…”

“…Mounting evidence also suggest that these modifications have site-specific and context-dependent roles, controlling local RNA–protein interactions by modulating the RNA structures where the interactions occur 15 – 19 . m 6 As play important roles in regulating various aspects of RNA biology, including RNA structure, splicing, translation, metabolism and translocation within cells and promote HIV-1 replication in general 3 , 44 . However, our current understanding is primarily based on indirect analyses of the phenotypic effects of perturbing m 6 A writers, readers or erasers in host cells, which overlook the potential site-specific roles of the modifications.…”

“…However, our current understanding is primarily based on indirect analyses of the phenotypic effects of perturbing m 6 A writers, readers or erasers in host cells, which overlook the potential site-specific roles of the modifications. Some findings remain controversial, showing inconsistent results depending on the replication stages, cell types and assays used in the studies 3 , 44 .…”

“…Since the late 1950s, more than 300 types of chemical modifications (epitranscriptomes) have been identified 1 , 2 , adding another layer of complexity to RNA biology. These modifications control a wide range of cellular and viral processes and are associated with more than 100 human diseases 2 , 3 . Studying these modifications, however, has been slow and laborious due to technical limitations inherent in the sequencing of native RNAs 4 .…”

“…Human immunodeficiency virus (HIV-1) has a substantially higher number of chemical modifications on its RNAs than typical cellular transcripts 5 , 6 . However, the evolutionary benefits and HIV-1-specific roles of these modifications in viral replication and various RNA functions remain unclear and sometimes even controversial, showing both pro- and anti-viral effects depending on the virus type, replication stage or tested cell type 3 , 7 – 11 . Most RNA modification studies so far have relied on indirect analyses of the phenotypic effects of perturbing host effectors (known as writers, erasers and readers) 6 , 8 , 10 , 12 – 14 , neglecting the potential site-specific and context-dependent roles of chemical modifications 15 – 19 .…”