Clade-specific differences in neurotoxicity of human immunodeficiency virus-1 B and C Tat of human neurons: significance of dicysteine C30C31 motif
Mamata Mishra MPhil
National Brain Research Centre, Manesar (Gurgaon), India
Search for more papers by this authorS. Vetrivel MSc
National Brain Research Centre, Manesar (Gurgaon), India
Search for more papers by this authorNagadenahalli B. Siddappa PhD
Jawaharlal Nehru, Centre for Advanced Scientific Research, Bangalore, India
Search for more papers by this authorUdaykumar Ranga PhD
Jawaharlal Nehru, Centre for Advanced Scientific Research, Bangalore, India
Search for more papers by this authorCorresponding Author
Pankaj Seth PhD
National Brain Research Centre, Manesar (Gurgaon), India
Molecular and Cellular Neuroscience, National Brain Research Centre (NBRC), NH-8, Nainwal Mode, Manesar, Haryana-122050, IndiaSearch for more papers by this authorMamata Mishra MPhil
National Brain Research Centre, Manesar (Gurgaon), India
Search for more papers by this authorS. Vetrivel MSc
National Brain Research Centre, Manesar (Gurgaon), India
Search for more papers by this authorNagadenahalli B. Siddappa PhD
Jawaharlal Nehru, Centre for Advanced Scientific Research, Bangalore, India
Search for more papers by this authorUdaykumar Ranga PhD
Jawaharlal Nehru, Centre for Advanced Scientific Research, Bangalore, India
Search for more papers by this authorCorresponding Author
Pankaj Seth PhD
National Brain Research Centre, Manesar (Gurgaon), India
Molecular and Cellular Neuroscience, National Brain Research Centre (NBRC), NH-8, Nainwal Mode, Manesar, Haryana-122050, IndiaSearch for more papers by this authorAbstract
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
Interpretation
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. Ann Neurol 2007
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