Abstract
RNA splicing is a critical step in the human immunodeficiency virus type 1 (HIV-1) replication cycle because it controls the expression of the complex viral proteome. The major 5′ splice site (5′ss) that is positioned in the untranslated leader of the HIV-1 RNA transcript is of particular interest because it is used for the production of the more than 40 differentially spliced subgenomic mRNAs. HIV-1 splicing needs to be balanced tightly to ensure the proper levels of all viral proteins, including the Gag-Pol proteins that are translated from the unspliced RNA. We previously presented evidence that the major 5′ss is regulated by a repressive local RNA structure, the splice donor (SD) hairpin, that masks the 11 nucleotides (nts) of the 5′ss signal for recognition by U1 small nuclear RNA (snRNA) of the spliceosome machinery. A strikingly different multiple-hairpin RNA conformation was recently proposed for this part of the HIV-1 leader RNA. We therefore inspected the sequence of natural HIV-1 isolates in search for support, in the form of base pair (bp) co-variations, for the different RNA conformations.
Highlights
The human immunodeficiency virus type 1 (HIV-1) untranslated leader RNA region can fold several stem-loop structures that have important regulatory functions, including the transacting responsive element (TAR), polyadenylation signal, dimerization initiation signal (DIS), splice donor (SD) and psi hairpins (Figure 1A) [1,2,3]
We here focus on the SD hairpin, which has been proposed to play a regulatory role in HIV-1 RNA splicing
(C) The 3WJ structure in which the SD region interacts with signal); (B) The alternative SDa hairpin structure. (C) The 3WJ structure in which the SD region upstream nucleotides; (A–C) The HIV-1 LAI prototype sequence is shown interacts with upstream nucleotides; (A–C) The HIV‐1 LAI prototype with the nts that form the U5-AUG long-distance interaction boxed in red (*, AUG start codon) and sequence is shown with the nts that form the U5‐AUG long‐distance interaction boxed in red
Summary
The human immunodeficiency virus type 1 (HIV-1) untranslated leader RNA region can fold several stem-loop structures that have important regulatory functions, including the transacting responsive element (TAR), polyadenylation signal (polyA), dimerization initiation signal (DIS), splice donor (SD) and psi hairpins (Figure 1A) [1,2,3]. Leader RNA. (A) The multiple hairpin structure in which the RNA folds the SD hairpin (N, 51 splice site cleavage site) and several other stem-loop structures that encode important hairpin (▲, 5’ splice site cleavage site) and several other stem‐loop structures that encode important replication signals (TAR, transacting responsive element; polyA, polyadenylation signal; PAS, primer replication signals (TAR, transacting responsive element; polyA, polyadenylation signal; PAS, activation signal; PBS, primer binding site; DIS, dimerization initiation signal; ψ, packaging signal); primer activation signal; PBS, primer binding site; DIS, dimerization initiation signal; ψ, packaging (B) The alternative SDa hairpin structure.
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