Functional consequences of natural sequence variation in the activation domain of HIV-1 Rev.
Initial infection with an attenuated form of human immunodeficiency virus type 1 (HIV-1) may give rise to some of the rare asymptomatic infections that have been observed. Recently, data have been presented suggesting that a persistent mutation in the essential activation domain of the HIV-1 Rev regulatory protein might have contributed to the maintenance of the asymptomatic state in one individual. Here, we have used a range of assays for in vivo Rev function to examine whether natural sequence variation in the normally highly conserved Rev activation domain can indeed affect Rev function. Analysis of five distinct natural 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 isolate of HIV-1, 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 isolates containing such sequence variation are likely to replicate less effectively.
Hua
J
J
Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710, USA.
Caffrey
J J
JJ
Cullen
B R
BR
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002461:Cell Line, Transformed; D002522:Chlorocebus aethiops; D015694:Gene Products, rev / Q000235:genetics* / Q000378:metabolism; D016370:Gene Products, rex / Q000378:metabolism; D014644:Genetic Variation; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins / Q000378:metabolism; D016601:RNA-Binding Proteins; D017422:Sequence Analysis, DNA; D014407:Tumor Cells, Cultured; D054321:rev Gene Products, Human Immunodeficiency Virus
C119724:AGFG1 protein, human; D002352:Carrier Proteins; D015694:Gene Products, rev; D016370:Gene Products, rex; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D054321:rev Gene Products, Human Immunodeficiency Virus