HIV-1: To Splice or Not to Splice, That Is the Question

Abstract

The transcription of the HIV-1 provirus results in only one type of transcript—full length genomic RNA. To make the mRNA transcripts for the accessory proteins Tat and Rev, the genomic RNA must completely splice. The mRNA transcripts for Vif, Vpr, and Env must undergo splicing but not completely. Genomic RNA (which also functions as mRNA for the Gag and Gag/Pro/Pol precursor polyproteins) must not splice at all. HIV-1 can tolerate a surprising range in the relative abundance of individual transcript types, and a surprising amount of aberrant and even odd splicing; however, it must not over-splice, which results in the loss of full-length genomic RNA and has a dramatic fitness cost. Cells typically do not tolerate unspliced/incompletely spliced transcripts, so HIV-1 must circumvent this cell policing mechanism to allow some splicing while suppressing most. Splicing is controlled by RNA secondary structure, cis-acting regulatory sequences which bind splicing factors, and the viral protein Rev. There is still much work to be done to clarify the combinatorial effects of these splicing regulators. These control mechanisms represent attractive targets to induce over-splicing as an antiviral strategy. Finally, splicing has been implicated in latency, but to date there is little supporting evidence for such a mechanism. In this review we apply what is known of cellular splicing to understand splicing in HIV-1, and present data from our newer and more sensitive deep sequencing assays quantifying the different HIV-1 transcript types.

The Splice of Life: Does RNA Processing Have a Role in HIV-1 Persistence?

“…More than 100 different viral transcripts can be detected in HIV-infected cells, all derived by alternative splicing from full-length unspliced (US) primary HIV-1 RNA transcripts that are transcribed from the integrated provirus ( Figure 1 ) [ 21 , 22 ]. As HIV-1 splicing has been covered in depth by several recent reviews [ 23 , 24 , 25 ], we will only provide a very brief overview here. Upon proviral integration, only short (2 kb) completely spliced, also called multiply spliced (MS), transcripts are initially produced that encode the regulatory proteins Tat, Rev, and Nef.…”

“…Other host factors that are differentially expressed in different cell types and individuals can, in theory, lead to variations in the HIV-1 splicing pattern, as well as in other steps of viral RNA processing, between cell types and/or infected individuals. However, experimental evidence for this is still lacking [ 23 ].…”

SARS-CoV-2 Portrayed Against HIV: Contrary Viral Strategies in Similar Disguise

“…In addition to these canonical ORFs encoding structural proteins, recent ribosomal-profiling has identified 23 translationally active unannotated SARS-CoV-2 ORFs with currently unknown function [125]. In contrast to SARS-CoV-2, the transcription of the integrated HIV-1 genome is carried out by cellular polymerases in the nucleus and through means of alternate splicing gives rise to over 50 viral RNA transcripts [126]. Governed by the cellular export machinery, only fully spliced RNA transcripts are exported from the nucleus for translation.…”

SARS-CoV-2 Portrayed against HIV: Contrary Viral Strategies in Similar Disguise

“…In addition to these canonical ORFs encoding structural proteins, recent ribosomal-profiling has identified 23 translationally active unannotated SARS-CoV-2 ORFs with currently unknown function [ 156 ]. In contrast to SARS-CoV-2, the transcription of the integrated HIV-1 genome is carried out by cellular polymerases in the nucleus and, through means of alternate splicing, gives rise to over 50 viral RNA transcripts [ 157 ]. Governed by the cellular export machinery, only fully spliced RNA transcripts are exported from the nucleus for translation.…”