title: Clade-specific differences in neurotoxicity of human immunodeficiency virus-1 B and C Tat of human neurons: significance of dicysteine C30C31 motif.
abstract: OBJECTIVE
  Human immunodeficiency virus-1 (HIV-1) causes mild to severe cognitive impairment and dementia. The transactivator viral protein, Tat, is implicated in neuronal death responsible for neurological deficits. Several clades of HIV-1 are unequally distributed globally, of which HIV-1 B and C together account for the majority of the viral infections. HIV-1-related neurological deficits appear to be most common in clade B, but not clade C prevalent areas. Whether clade-specific differences translate to varied neuropathogenesis is not known, and this uncertainty warrants an immediate investigation into neurotoxicity on human neurons of Tat derived from different viral clades
  
  
  METHODS
  We used human fetal central nervous system progenitor cell-derived astrocytes and neurons to investigate effects of B- and C-Tat on neuronal cell death, chemokine secretion, oxidative stress, and mitochondrial membrane depolarization by direct and indirect damage to human neurons. We used isogenic variants of Tat to gain insights into the role of the dicysteine motif (C30C31) for neurotoxic potential of Tat
  
  
  RESULTS
  Our results suggest clade-specific functional differences in Tat-induced apoptosis in primary human neurons. This study demonstrates that C-Tat is relatively less neurotoxic compared with B-Tat, probably as a result of alteration in the dicysteine motif within the neurotoxic region of B-Tat
  
  
  CONCLUSIONS
  This study provides important insights into differential neurotoxic properties of B- and C-Tat, and offers a basis for distinct differences in degree of HIV-1-associated neurological deficits observed in patients in India. Additional studies with patient samples are necessary to validate these findings.
authors: National Brain Research Centre, Manesar (Gurgaon), India.
authors: Mamata
authors: M
authors: Mishra
authors: S
authors: S
authors: Vetrivel
authors: Nagadenahalli B
authors: NB
authors: Siddappa
authors: Udaykumar
authors: U
authors: Ranga
authors: Pankaj
authors: P
authors: Seth
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D002478:Cells, Cultured; D003545:Cysteine / Q000235:genetics*; D015696:Gene Products, tat / Q000235:genetics* / Q000633:toxicity*; D015497:HIV-1 / Q000145:classification* / Q000235:genetics*; D006801:Humans; D009474:Neurons / Q000473:pathology* / Q000502:physiology / Q000821:virology; D013234:Stem Cells / Q000473:pathology / Q000821:virology
chemical_list: D015696:Gene Products, tat; D003545:Cysteine