Abstract
RNA secondary structure plays a central role in the replication and metabolism of all RNA viruses, including retroviruses like HIV-1. However, structures with known function represent only a fraction of the secondary structure reported for HIV-1NL4-3. One tool to assess the importance of RNA structures is to examine their conservation over evolutionary time. To this end, we used SHAPE to model the secondary structure of a second primate lentiviral genome, SIVmac239, which shares only 50% sequence identity at the nucleotide level with HIV-1NL4-3. Only about half of the paired nucleotides are paired in both genomic RNAs and, across the genome, just 71 base pairs form with the same pairing partner in both genomes. On average the RNA secondary structure is thus evolving at a much faster rate than the sequence. Structure at the Gag-Pro-Pol frameshift site is maintained but in a significantly altered form, while the impact of selection for maintaining a protein binding interaction can be seen in the conservation of pairing partners in the small RRE stems where Rev binds. Structures that are conserved between SIVmac239 and HIV-1NL4-3 also occur at the 5′ polyadenylation sequence, in the plus strand primer sites, PPT and cPPT, and in the stem-loop structure that includes the first splice acceptor site. The two genomes are adenosine-rich and cytidine-poor. The structured regions are enriched in guanosines, while unpaired regions are enriched in adenosines, and functionaly important structures have stronger base pairing than nonconserved structures. We conclude that much of the secondary structure is the result of fortuitous pairing in a metastable state that reforms during sequence evolution. However, secondary structure elements with important function are stabilized by higher guanosine content that allows regions of structure to persist as sequence evolution proceeds, and, within the confines of selective pressure, allows structures to evolve.
Highlights
RNA secondary structures play fundamental roles in the replication of all positive-strand RNA viruses
The human immunodeficiency virus type 1 (HIV-1) is no exception, and wellcharacterized RNA structures within the coding domains of the genome play critical roles in regulation of replication. These include a structure in the env gene, the Rev Response Element (RRE), that binds the viral protein Rev leading to the transport of unspliced and singly-spliced viral mRNA out of the nucleus [1,2], and a hairpin structure preceded by a poly(U) slippery sequence that mediates a frameshift during synthesis of the Gag-Pro-Pol polyprotein [3,4]
This suggests that most of the genome is in a metastable state that refolds during sequence evolution
Summary
RNA secondary structures play fundamental roles in the replication of all positive-strand RNA viruses. The human immunodeficiency virus type 1 (HIV-1) is no exception, and wellcharacterized RNA structures within the coding domains of the genome play critical roles in regulation of replication. These include a structure in the env gene, the Rev Response Element (RRE), that binds the viral protein Rev leading to the transport of unspliced and singly-spliced viral mRNA out of the nucleus [1,2], and a hairpin structure preceded by a poly(U) slippery sequence that mediates a frameshift during synthesis of the Gag-Pro-Pol polyprotein [3,4]. The untranslated regions (UTRs) of HIV-1 and simian immunodeficiency virus (SIV) contain the TAR hairpin, which recruits the Tat protein to modulate transcription [5,6] (reviewed in [7]) and other stem-loop structures that are important
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