Naturally occurring genotypes of the human immunodeficiency virus type 1 long terminal repeat display a wide range of basal and Tat-induced transcriptional activities

Abstract

The primary body of information on the structure of human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR)/gag leader genotypes has been determined from the analysis of cocultivated isolates. Functional studies of this regulatory portion of the provirus have been derived from the study of in vitro-generated mutations of laboratory-adapted molecular clones of HIV-1. We have performed a longitudinal analysis of molecular clones from the LTR/gag leader region amplified directly from the peripheral blood of four patients over three years. We have found a remarkable number of point mutations and length

Human immunodeficiency virus type 1 long terminal repeat variants from 42 patients representing all stages of infection display a wide range of sequence polymorphism and transcription activity

“…Of the USF site variants, 30% were not represented in the LANL database (40). This contrasts with a previous observation that the USF consensus is strictly conserved in the HIV-1 5Ј LTR in vivo (9) on the basis of a limited longitudinal analysis of four patients (38). The Ets 1 motif core, 5Ј-GGA-3Ј (on the negative strand; nucleotides Ϫ144 to Ϫ146) (23) (Fig.…”

“…In particular, the high-level variability of the USF binding site suggests a dispensable role in vivo. Length polymorphism in the SP-1 region was associated with lower-level activity, in contrast to the increased transcription reported by another group for a similar polymorphism in this region (38). This may be reconciled by differences between the SP-1 binding site detected by those authors and the imperfect SP-1 sites we detected.…”

“…In agreement with the importance of the loop and bulge of TAR (22), we found that polymorphisms to this region correlated with impaired Tat responsiveness. Other workers have also noted an unexpectedly large number of LTRs that are unresponsive to Tat (37,38). Perhaps Tat-unresponsive LTRs play a role at some point in vivo through low-level gene expression, hence evading more rapid clearance by the host immune system.…”

“…Koken et al (28) screened for 5Ј LTR length variants from 17 patients and identified a variant with a fourth SP-1 site that could outgrow an isogenic construct with three SP-1 sites, as well as length variants with a 5Ј-CTG-3Ј motif insertion 5Ј of NF-B sites that could confer a marginal decrease in proviral 5Ј LTR transcription and replicative ca-pacity. Similarly, Michael et al (38) have described deletions, insertions, and point mutations to the core enhancer or promoter and TAR sequences in four patients over 3 years and noted that partial LEF-1 duplication variants (with a 5Ј-ACTGC-3Ј motif) had decreased proviral 5Ј-LTR-driven transcription. Patterns to LTR variants selected in vivo are suggested by recent studies by Ait-Khaled et al (1,2) demonstrating tissue-compartmentalized phylogenetic clustering of LTR variants in four patients and one patient, respectively.…”

“…In contrast to longitudinal studies of naturally occurring HIV-1 LTR sequences from a few patients at one stage of disease or one patient throughout a window of disease progression (1,10,11,28,(36)(37)(38), we investigated a cross section of 42 patients at all stages of HIV-1 infection. Here we report on the sequence polymorphism of 478 LTRs, on the transcription activities for a subset of these LTRs, and on altered binding of nuclear factors in vitro to some of the novel in vivo polymorphisms found to correspond with altered transcription.…”