Brain-derived human immunodeficiency virus-1 Tat exerts differential effects on LTR transactivation and neuroimmune activation
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.
Keywordsastrocyte chemokine cytokine HIV-1 LTR macrophage microarray Tat
Unable to display preview. Download preview PDF.
- Aldovini A, Feinberg MB (1990). Techniques in HIV research. Stockton Press: New York.Google Scholar
- Burdo TH, Nonnemacher M, Irish BP, Choi CH, Krebs FC, Gartner S, Wigdahl B (2004). High-affinity interaction between HIV-1 Vpr and specific sequences that span the C/EBP and adjacent NF-kappaB sites within the HIV-1 LTR correlate with HIV-1-associated dementia. DNA Cell Biol 23: 261–269.CrossRefPubMedGoogle Scholar
- Liu J, Blackhall F, Seiden-Long I, Jurisica I, Navab R, Liu N, Radulovich N, Wigle D, Sultan M, Hu J, Tsao MS, Johnston MR (2004). Modeling of lung cancer by an orthotopically growing H460SM variant cell line reveals novel candidate genes for systemic metastasis. Oncogene 23: 6316–6324.CrossRefPubMedGoogle Scholar
- Marchio S, Alfano M, Primo L, Gramaglia D, Butini L, Gennero L, De Vivo E, Arap W, Giacca M, Pasqualini R, Bussolino F (2005). Cell surface-associated Tat modulates HIV-1 infection and spreading through a specific interaction with gp120 viral envelope protein. Blood 105: 2802–2811.CrossRefPubMedGoogle Scholar
- van der Zee R, Anderton SM, Buskens CAF, Alonso de Velasco E, van Eden W (1994). Heat shock protein T cell epitopes as immunogenic carriers in subunit vaccines. In: Twenty-third European peptide symposium. Maya HLS, (ed): Leiden.Google Scholar