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-1beta. 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.
Boven
Leonie A
LA
Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands.
Noorbakhsh
Farshid
F
Bouma
Gerben
G
van der Zee
Ruurd
R
Vargas
Diana L
DL
Pardo
Carlos
C
McArthur
Justin C
JC
Nottet
Hans S L M
HS
Power
Christopher
C
D015526:AIDS Dementia Complex / Q000276:immunology / Q000378:metabolism / Q000821:virology; D000595:Amino Acid Sequence; D001253:Astrocytes / Q000378:metabolism / Q000821:virology; D001921:Brain / Q000378:metabolism / Q000821:virology; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism; D015536:Down-Regulation; D015967:Gene Expression Regulation, Viral; D015696:Gene Products, tat / Q000737:chemistry / Q000235:genetics*; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D016325:HIV Long Terminal Repeat / Q000235:genetics*; D015497:HIV-1 / Q000502:physiology*; D006497:Heparan Sulfate / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism / Q000821:virology; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D015533:Transcriptional Activation; D014779:Virus Replication; D054322:tat Gene Products, Human Immunodeficiency Virus
D018932:Chemokine CCL2; D015696:Gene Products, tat; D006497:Heparan Sulfate; D053583:Interleukin-1beta; D054322:tat Gene Products, Human Immunodeficiency Virus; C111835:CCL2 protein, human