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.

Keywords: HIV-1; N6-methyladenosine; epitranscriptomic RNA modification; innate immunity; virus–host interactions.

Figure 1

Summary of m⁶A mapping in HIV-1 RNA. The position of the m⁶A peaks on the HIV-1 genome is illustrated by a schematic diagram that is drawn to scale. The HIV-1_NL4-3 strain genome was used as a reference to compare data reported by each publication. Black boxes represent predicted peak locations based on various sequencing approaches using RNA purified from (A) HIV-1-infected cells or (B) HIV-1 virions. Where possible, boxes represent exact reported peak width [25,26,27,28,31,33]. Other boxes are drawn based on peak calling maps from individual publications [29,30].

Figure 2

Post-integration regulation of HIV-1 RNA by m⁶A regulators. (1) Viral RNA is methylated by the methyltransferase complex in the nucleus (for simplicity, only one m⁶A is shown on viral transcripts). (2) YTHDC1 regulates the splicing of full-length and incompletely spliced HIV-1 RNA but does not affect multiply spliced transcripts. (3) YTHDF1, 2, and 3 proteins positively regulate HIV-1 RNA abundance and viral protein synthesis. (4) Gag is imported into the nucleus and interacts with FTO to demethylate full-length HIV-1 RNA. (5 and 6) Gag preferentially interacts with full-length HIV-1 RNA and is packaged into progeny virions.