Abstract
A distance constrained secondary structural model of the ≈10 kb RNA genome of the HIV-1 has been predicted but higher-order structures, involving long distance interactions, are currently unknown. We present the first global RNA secondary structure model for the HIV-1 genome, which integrates both comparative structure analysis and information from experimental data in a full-length prediction without distance constraints. Besides recovering known structural elements, we predict several novel structural elements that are conserved in HIV-1 evolution. Our results also indicate that the structure of the HIV-1 genome is highly variable in most regions, with a limited number of stable and conserved RNA secondary structures. Most interesting, a set of long distance interactions form a core organizing structure (COS) that organize the genome into three major structural domains. Despite overlapping protein-coding regions the COS is supported by a particular high frequency of compensatory base changes, suggesting functional importance for this element. This new structural element potentially organizes the whole genome into three major domains protruding from a conserved core structure with potential roles in replication and evolution for the virus.
Highlights
The RNA genome of HIV-1 is situated in the viral capsid as two non-covalent linked positive stranded RNAs, with a length of ≈10 kb
In the prediction by PPfold 3.1, the evolutionary covariation information derived from the alignment was weighted with the SHAPE data measured for one B-strain sequence, integrating the available data for the best secondary structure model for this particular sequence
The consensus structure prediction does not necessarily correspond to the optimal structure of each individual strain, and our result is biased towards the optimal structure for the Bstrain sequence for which the SHAPE data were available
Summary
The RNA genome of HIV-1 is situated in the viral capsid as two non-covalent linked positive stranded RNAs, with a length of ≈10 kb. It encodes several layers of information required for the viral replication cycle both for instructing protein synthesis and as functional RNA elements. The highly conserved transactivator region (TAR) hairpin, which recruits the viral Tat protein [3,4], is positioned at the 5 end of the genome This is followed by the polyA-hairpin containing a suppressed polyadenylation signal, but which plays an important role in nuclear export, dimerization and packaging [5]. Towards the 3 end of the genome in the Env coding region, the Rev response element (RRE) [6], composed of ≈350 nucleotides, forms a binding platform for multiple viral Rev proteins, enabling the nuclear export of the unspliced and singly spliced
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