Distinct HIV-1 long terminal repeat quasispecies present in nervous tissues compared to that in lung, blood and lymphoid tissues of an AIDS patient

Ait‐Khaled, Mounir; McLaughlin, James E.; Johnson, Margaret; Emery, Vincent

doi:10.1097/00002030-199507000-00002

Cited by 67 publications

(49 citation statements)

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“…In brain sample 2297, we sequenced three clones with an apparent extra two ATF/CREB sites embedded in 23 ± 24 bp insertions at position 7126 (Figure 3). These insertions interrupted the LEF-1 site, and were similar in location and DNA sequence to the LEF-1 duplications described in blood samples by others (Ait-Khaled et al, 1995;Delassus et al, 1991;Estable et al, 1996;Golub et al, 1990;Michael et al, 1994). The insertions differed from each other at only a single base, and shared 15 bases with the 28 bp insertion in clone, 94299, derived from the blood of an unrelated patient (Figure 3).…”

Section: Multiplication Of Atf/cre Transcription Factor Binding Sitessupporting

confidence: 78%

“…The 16 comparable LTR sequences (Figure 1) in clade B of the Los Alamos HIV-1 sequence database (Myers et al, 1995), derived from multiple tissues and sources, shared 93% similarity with one another, and with our brain clones. When placed on our phylogenetic tree, the sequences described by Ait-Khaled et al (1995), derived from spinal cord and dorsal root ganglia of a single patient, occupied a branch (group F) separate from our clones and equally distant from IIIB, JR-FL and JR-CSF.…”

Section: Resultsmentioning

confidence: 93%

“…As with the HIV-1 env gene (Ball et al, 1994;Epstein et al, 1991;Korber et al, 1994;Pang et al, 1991), HIV-1 LTR DNA sequences appear to evolve independently in the CNS (Ait-Khaled et al, 1995). In other retroviruses, variant LTR sequences have been associated with tissue tropism and disease potential Lenz et al, 1984;Small et al, 1989), sometimes in association with the env gene (Poliquin et al, 1992;Portis et al, 1990;Yuen et al, 1986).…”

Section: Introductionmentioning

confidence: 99%

“…In order to de®ne further the spectrum of sequences potentially relevant to HIV-1 gene expression in the CNS, we analyzed HIV-1 LTR DNA isolated from the brains of four HIV-1-infected adult patients. The sequences were aligned and compared by phylogenetic analysis to themselves (intra-brain and inter-brain), the CNS-derived clones described by Ait-Khaled et al (1995), and to 16 previously published LTR sequences deposited in the Los Alamos HIV-1 sequence databank (Myers et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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HIV-1 LTR DNA sequence variation in brain-derived isolates

Corboy¹,

Garl²

1997

J Neurovirol

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Isolates of human immunode®ciency virus (HIV-1) derived from the central nervous system (CNS) display properties distinctive from blood-derived isolates, including a high incidence of macrophage tropism in CNS isolates. Macrophage tropism is a result, in part, of DNA sequence variation in the HIV-1 envelope glycoprotein gene, but evidence also exists suggesting differences in the long terminal repeat (LTR) may contribute to differential gene expression. To investigate the nature of HIV-1 LTR sequence variation in the brain, we have sequenced bases 7374 to +43 of the LTR from the brains of four HIV-1-infected patients. A total of 56 clones were derived from either both gray and white matter (three brains) or white matter alone (one brain), and these sequences were compared to 17 published sequences derived from multiple sources. A total of ®ve LTR quasispecies were found. Overall, there was a signi®cant amount of sequence variation both within and between brains, comparable to that seen in quasispecies of the envelope glycoprotein derived from blood or brain. The vast majority of the variation was seen in regions upstream from the two NF-kB sites. Compared to the blood-derived, T cell-tropic IIIB LTR, a majority of clones from two or more of the brains shared 11 unique substitutions in transcription factor binding sites, of which eight were shared with the CNSderived clones JR-CSF and JR-FL and altered the NF-AT and LEF-1 transcription factor binding sites. These ®ndings correlate with published functional studies showing CNS-derived HIV-1 LTRs are distinct from the blood-derived IIIB LTR, and represent a starting point for future studies designed to determine which LTR sequence variations are associated with cellspeci®c differences in gene expression in the CNS.

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Section: Multiplication Of Atf/cre Transcription Factor Binding Sitessupporting

confidence: 78%

Section: Resultsmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

HIV-1 LTR DNA sequence variation in brain-derived isolates

Corboy¹,

Garl²

1997

J Neurovirol

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“…3 Several studies have previously described the compartmentalization of LTR sequences between different anatomical sites using phylogenetic analyses. 9,10 This suggests that LTRs may evolve in a tissue-specific manner to reflect the different transcriptional factors present within their resident cells. Within T lymphocytes, inducible LTR regulation is predominantly linked to members of the NF-jB transcription factor family and is dependent on the Sp binding motif.…”

mentioning

confidence: 99%

Reduced Basal Transcriptional Activity of Central Nervous System-Derived HIV Type 1 Long Terminal Repeats

Gray

Cowley

Crespan

et al. 2013

AIDS Research and Human Retroviruses

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New evidence indicates that astrocytes of the central nervous system (CNS) are extensively infected with human immunodeficiency virus type 1 (HIV-1) in vivo. Although no new virus is produced, this nonproductive or restricted infection contributes to the pathogenesis of HIV-associated dementia (HAD) and compromises virus eradication strategies. The HIV-1 long terminal repeat (LTR) plays a critical role in regulating virus production from infected cells. Here, we determined whether LTRs derived from CNS and non-CNS compartments are genetically and functionally distinct and contribute to the restricted nature of astrocyte infection. CNS-and/or non-CNS-derived LTRs (n = 82) were cloned from primary HIV-1 viruses isolated from autopsy tissues of seven patients who died with HAD. Phylogenetic analysis showed interpatient and intrapatient clustering of LTR nucleotide sequences. Functional analysis showed reduced basal transcriptional activity of CNS-derived LTRs in both astrocytes and T cells compared to that of non-CNS-derived LTRs. However, LTRs were heterogeneous in their responsiveness to activation by Tat. Therefore, using a relatively large, independent panel of primary HIV-1 LTRs derived from clinically well-characterized subjects, we show that LTRs segregate CNS-from non-CNSderived tissues both genetically and functionally. The reduced basal transcriptional activity of LTRs derived from the CNS may contribute to the restricted HIV-1 infection of astrocytes and latent infection within the CNS. These findings have significance for understanding the molecular basis of HIV-1 persistence within cellular reservoirs of the CNS that need to be considered for strategies aimed at eradicating HIV-1.

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Quantitative differences in the distribution of zidovudine resistance mutations in multiple post-mortem tissues from AIDS patients

et al. 1998

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Replication of HIV introduces errors into the genome which are responsible for conferring a growth advantage over wildtype virus when drugs such as zidovudine (ZDV) exert a selective pressure. The molecular basis for HIV-1 resistance to ZDV has been mapped to codons 41, 67, 70, 215 and 219 of the reverse transcriptase gene both in vitro and in clinical samples of blood. This study has investigated the relationship between the quantitative prevalence of ZDV resistance in multiple organs of the same individual. Proviral HIV-1 load was measured by quantitative-competitive PCR in 90 samples from organs of 11 patients dying with AIDS. Nine of these patients had been prescribed zidovudine. The distribution of wildtype and mutant sequences at the positions 41, 67, 70, 215 and 219 of the reverse transcriptase was assessed using a point mutation assay. The results showed that the highest proviral loads were predominately found in lymph node, spleen and lung and there was a significant association between viral load and resistance to ZDV (P=0.008). Inter-organ distribution of wildtype and mutant sequences at codons 41, 67, 70, 215 and 219 was frequently not uniform and in some patients differed markedly between the lymphoreticular system and other organs. These results demonstrate that treatment of HIV-1 infection with zidovudine does not exert uniform selective pressures in multiple organs. These findings have implications for the interpretation of resistance data and design of treatment strategies for HIV, arguing in particular that alterations in therapeutic regimens should consider the likelihood of different resistance patterns being present in multiple sites within the same individual.

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Distinct HIV-1 long terminal repeat quasispecies present in nervous tissues compared to that in lung, blood and lymphoid tissues of an AIDS patient

Cited by 67 publications

References 0 publications

HIV-1 LTR DNA sequence variation in brain-derived isolates

HIV-1 LTR DNA sequence variation in brain-derived isolates

Reduced Basal Transcriptional Activity of Central Nervous System-Derived HIV Type 1 Long Terminal Repeats

Quantitative differences in the distribution of zidovudine resistance mutations in multiple post-mortem tissues from AIDS patients

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