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

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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.

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Authors and Affiliations

  1. Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands

    Leonie A. Boven

  2. Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada

    Leonie A. Boven & Christopher Power

  3. Department of Immunology, Tehran University of Medical Sciences, Tehran, Iran

    Farshid Noorbakhsh

  4. Eijkman-Winkler Institute, Section of Neuroimmunology, University Medical Center, Utrecht, The Netherlands

    Gerben Bouma & Hans S. L. M. Nottet

  5. Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands

    Ruurd van der Zee

  6. Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA

    Diana L. Vargas, Carlos Pardo & Justin C. McArthur

  7. Department of Medicine, University of Alberta Heritage Medical Research Centre, Room 611, T6G 2S2, Edmonton, AB, Canada

    Christopher Power

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  1. Leonie A. Boven
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  2. Farshid Noorbakhsh
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  3. Gerben Bouma
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  4. Ruurd van der Zee
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  5. Diana L. Vargas
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  6. Carlos Pardo
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  7. Justin C. McArthur
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  8. Hans S. L. M. Nottet
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  9. Christopher Power
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Correspondence to Christopher Power.

Additional information

LAB was supported by an Alberta Heritage Foundation for Medical Research (AHFMR)/ Canadian Institutes of Health Research (CIHR) Fellowship.

CP holds a Canada Research Chair (T1) in Neurological Infection and Immunity and is an AHFMR Senior Scholar.

These studies were supported by grants from the CIHR (CP) and CANFAR (CP).

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Boven, L.A., Noorbakhsh, F., Bouma, G. et al. Brain-derived human immunodeficiency virus-1 Tat exerts differential effects on LTR transactivation and neuroimmune activation. Journal of NeuroVirology 13, 173–184 (2007). https://doi.org/10.1080/13550280701258399

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  • DOI: https://doi.org/10.1080/13550280701258399

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