Publications & Reports

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, Churchill MJ
Monash University, Department of Biochemistry and Molecular Biology, Clayton, Victoria, Australia; lachlang@burnet.edu.au.

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 non-productive 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 7 patients who died with HAD. Phylogenetic analysis of LTR nucleotide sequences showed inter-patient clustering and intra-patient anatomical compartmentalization. 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 are compartmentalized between CNS- and 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.

Full text on PubMedCentral at

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3552182/

Publication

  • Journal: AIDS Research and Human Retroviruses
  • Published: 01/01/2013
  • Volume: 29
  • Issue: 2
  • Pagination: 365-370

Download