Structural Differentiation of the HIV-1 Poly(A) Signals

Abstract

The Human Immunodeficiency Virus Type 1 (HIV-1) encodes the polyadenylation (poly(A)) signal (AAUAAA) within the highly conserved untranslated region (UTR) at both 5′ and 3′ terminals of the viral transcript. In polyadenylation, an RNA transcript is cleaved and then elongated with adenine nucleotides while repression of the 5′ signal and utilization of the 3′ signal occurs. Because experimental studies have yet to analyze the structures of both 5′ and 3′ signals from a global perspective, other structural conformations involving these signals may exist and could be pivotal to understanding key functional processes. To distinguish the differential regulation of the 5′ and 3′ poly(A) signals, we studied the structural tendencies of both the 5′ and 3′ UTR in HIV-1. Through computational folding predictions of multiple HIV-1 strains using the Massively Parallel Genetic Algorithm (MPGAfold) capable of dynamically elucidating key alternative conformations, the 5′ poly(A) signal was found to be dominantly occluded in a hairpin loop while the 3′ poly(A) signal showed variability between hairpin and linear conformations with a propensity for the linear structure with an asymmetric internal loop. Furthermore, the energies and predictions of these structures indicate that the poly(A) signals have some metastable characteristics indicating an ability to switch into different conformations that can regulate viral function.