Regulation of human immunodeficiency virus type 1 gene expression by clade-specific Tat proteins.
The major group of human immunodeficiency virus type 1 (HIV-1) strains that comprise the current global pandemic have diversified during their worldwide spread into at least 10 distinct subtypes, or clades. Subtype C predominates in sub-Saharan Africa and is responsible for the majority of worldwide HIV-1 infections, subtype B predominates in North America and Europe, and subtype E is prevalent in Southeast Asia. Significant amino acid variations have been observed among the clade-specific Tat proteins. For the present study, we examined clade-specific interactions between Tat, transactivation-responsive (TAR) element, and P-TEFb proteins and how these interactions may modulate the efficiency of HIV-1 transcription. Clade-specific Tat proteins significantly modified viral gene expression. Tat proteins derived from HIV-1 clades C and E were strong transactivators of long terminal repeat (LTR) activity; Tat E also had a longer half-life than the other Tat proteins and interacted more efficiently with the stem-loop TAR element. Chimeric Tat proteins harboring the Tat E activation domain were strong transactivators of LTR expression. While Tat B, C, and E were able to rescue a Tat-defective HIV-1 proviral clone, Tat E was significantly more efficient at rescue than Tat C, possibly due to the relative stability of the Tat protein. Swapping the activation domains of Tat B, C, and E identified the cyclin T1 association domain as a critical determinant of the transactivation efficiency and of Tat-defective HIV-1 provirus rescue.
McGill AIDS Center, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, 3755 Cote Ste. Catherine, Montreal, Quebec, Canada H3T1E2.
Yan
Y
Desfosses
Mayra
M
Solis
Qiang
Q
Sun
Nathalie
N
Grandvaux
Carine
C
Van Lint
Arsene
A
Burny
Anne
A
Gatignol
Mark A
MA
Wainberg
Rongtuan
R
Lin
John
J
Hiscott
D000595:Amino Acid Sequence; D015967:Gene Expression Regulation, Viral; D015696:Gene Products, tat / Q000737:chemistry / Q000502:physiology*; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators; D054322:tat Gene Products, Human Immunodeficiency Virus; D042925:Positive Transcriptional Elongation Factor B