Brain-derived human immunodeficiency virus-1 Tat exerts differential effects on LTR transactivation and neuroimmune activation

Leonie Boven, Farshid Noorbakhsh, Gerben Bouma, Ruurd van der Zee, Diana L. Vargas, Carlos Pardo, Justin C. McArthur, Hans S.L.M. Nottet, Christopher Power

Research output: Contribution to journalArticlepeer-review

Abstract

Molecular diversity within brain-derived HIV-1 sequences is highly variable depending on the individual gene examined and the neurological status of the patient. Herein, we examined different brain-derived human immunodeficiency virus (HIV)-1 tat sequences in terms of their effects on LTR transactivation and host gene induction in neural cells. Astrocytic and monocytoid cells co-transfected with prototypic tat clones derived from non-demented (ND) (n = 3) and demented (HAD) (n = 3) AIDS patients and different HIV-LTR constructs revealed that LTR transactivation mediated by tat clones derived from HAD patients was decreased (p < 0.05). A Tat-derived peptide containing the amino acid 24-38 domain from a ND clone caused down-regulation of the LTR transactivation (p < 0.05) in contrast to peptides from other Tat regions derived from HAD and ND tat clones. Both brain-derived HAD and ND tat constructs were able to induce the host immune genes, MCP-1 and IL-1β. Microarray analysis revealed several host genes were selectively upregulated by a HAD-derived tat clone including an enzyme mediating heparan sulphate synthesis, HS3ST3B1 (p < 0.05), which was also found to be increased in the brains of patients with HAD. Expression of the pro-apoptotic gene, PDCD7, was reduced in cells transfected with the HAD-derived tat clone and moreover, this gene was also suppressed in monocytoid cells infected with a neurotropic HIV-1 strain. Thus, mutations within the HIV-1 tat gene may exert pathogenic effects contributing to the development of HAD, which are independent of its effects on LTR transactivation.

Original languageEnglish (US)
Pages (from-to)173-184
Number of pages12
JournalJournal of neurovirology
Volume13
Issue number2
DOIs
StatePublished - Mar 2007

Keywords

  • Astrocyte
  • Chemokine
  • Cytokine
  • HIV-1
  • LTR
  • Macrophage
  • Microarray
  • Tat

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Virology

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