Heterogeneity of HIV-1 Rev response element

We compiled all the RRE sequences of HIV-1 in the HIV Sequence Database and analyzed for base variation frequency at each nucleotide position. Positions with high frequency of base alteration scattered throughout the region, but primary sequences of almost all bases in stem IIA, Rev-binding bubble, and most of the stem region of stem-loop III were highly conserved. Comparing to HXB2 secondary structure, basepair-disrupting mutations did not distribute evenly in every region of the RRE. Stem I, stem IIB outside the Rev-binding site, stem IIC, and proximal parts of stem IV and V were more variable, while stem IIA, stem III, and distal parts of stem IV and V were highly conserved. These data indicated that RREs are structurally heterogeneous. The uneven distribution of variation in both primary sequence and the stem structure put forward highly conserved sites that might be more crucial to the function of RRE than the less conserved parts.