Reduced basal transcriptional activity of central nervous system-derived HIV-1 long terminal repeats

Gray, L, Cowley, D, Crespan, E, Welsh, C, Mackenzie, C, Wesselingh, S, Gorry, P and Churchill, M 2013, 'Reduced basal transcriptional activity of central nervous system-derived HIV-1 long terminal repeats', AIDS Research and Human Retroviruses, vol. 29, no. 2, pp. 365-370.


Document type: Journal Article
Collection: Journal Articles

Title Reduced basal transcriptional activity of central nervous system-derived HIV-1 long terminal repeats
Author(s) Gray, L
Cowley, D
Crespan, E
Welsh, C
Mackenzie, C
Wesselingh, S
Gorry, P
Churchill, M
Year 2013
Journal name AIDS Research and Human Retroviruses
Volume number 29
Issue number 2
Start page 365
End page 370
Total pages 6
Publisher Mary Ann Liebert Publishers
Abstract 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-CNS-derived 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.
Subject Medical Virology
DOI - identifier 10.1089/aid.2012.0138
Copyright notice © 2013 Mary Ann Liebert, Inc
ISSN 0889-2229
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