Drastic decrease of transcription activity due to hypermutated long terminal repeat (LTR) region in different HIV-1 subtypes and recombinants

Abstract

Transcriptional activation of HIV-1 gene expression is partially controlled by the interaction between viral and cellular transcription factors acting at HIV-1 long terminal repeat (LTR) sequences. HIV-1 subtyping at LTR region and nucleotide LTR variability from clinical samples in 48 subjects carrying different HIV-1 subtypes (9A, 5C, 3D, 3F, 21G, 2H, 3J and 2 undefined) at the protease (PR) gene, were performed. LTR sequences from each HIV-1 clade were cloned in luciferase-expression vectors to determine basal and Tat-induced transcriptional activities in the presence and absence of PMA stimulation. A high number (37.8%) of recombinants at LTR/PR regions were identified. All HIV-1 promoters presented low basal transcriptional activity that was nevertheless induced by Tat and PMA. LTR activity was similar across the majority of HIV-1 variants in response to Tat and cell activation. Only subtype C and CRF01_AE LTRs presented higher basal and induced-PMA transcription activities than HXB2 clade B promoter. No basal or Tat/PMA induced activity was found in those promoters presenting G to A hypermutation compared to the wild type promoter activities. G to A hypermutation at some important transcription binding-factor sites within LTR compromised the activity of the viral promoter, decreasing the in vitro viral transcription of the luciferase gene.