FUNCTIONAL CONSEQUENCES OF NATURAL SEQUENCE VARIATION IN THE ACTIVATION DOMAIN OF HIV-1 REV

Initial infection with an attenuated form of human immunodeficiency vi rus type 1 (HIV-I) may give rise to some of the rare asymptomatic infe ctions that have been observed. Recently, data have been presented sug gesting that a persistent mutation in the essential activation domain of the HIV-I Rev regulatory protein might have contributed to the main tenance of the asymptomatic state in one individual. Here, we have use d a range of assays for in vivo Rev function to examine whether natura l sequence variation in the normally highly conserved Rev activation d omain can indeed affect Rev function. Analysis of five distinct natura l sequence variants of the Rev domain demonstrated that each produced a two- to fourfold drop in Rev function when compared to the consensus activation domain sequence. A sixth sequence, reported for the MN iso late of HIV-I, proved entirely inactive. However, resequencing of this region of the MN genome revealed that this isolate actually encodes a consensus Rev activation domain. Overall, these data reveal that even natural sequence variation in the essential Rev activation domain can result in significantly reduced Rev function and suggest that isolate s containing such sequence variation are likely to replicate less effe ctively. (C) 1996 Academic Press, Inc.