Differential induction of rat neuronal excitotoxic cell death by human immunodeficiency virus type 1 clade B and C tat proteins.
In the absence of effective antiretroviral therapy, infection with clade B human immunodeficiency virus (HIV-1) infection commonly progresses to AIDS dementia. However, in India, where clade C infection is most prevalent, severe cognitive impairment due to HIV-1 is reported to be less prevalent. The Tat protein of HIV-1, which is released from HIV-1-infected macrophages, is thought to play a major role in the disruption of neuronal function as well as in the infiltration of macrophages associated with advanced neuropathogenesis. Clade B Tat is excitotoxic to hippocampal neurons by potentiating N-methyl-d-aspartate-induced currents of the zinc-sensitive NR1/NR2A N-methyl-d-aspartate receptor in a zinc-binding-dependent mechanism. This study characterizes the zinc-binding properties of clade C Tat protein. Using ultraviolet spectroscopy and the Ellman reaction, we show that clade C Tat protein binds just one zinc ion per monomer. We then investigated the ability of clade C Tat to block the inhibition of N-methyl-d-aspartate receptors from zinc antagonism through ion chelation. Although clade C Tat enhanced N-methyl-d-aspartate-mediated rat hippocampus neuronal toxicity in the presence of zinc, the increase was significantly less than that observed with clade B Tat. These findings suggest that the observed differences in neuropathogenesis found with HIV-1 clade C infection compared to clade B may, in part, be due to a decrease in Tat-mediated neurotoxicity.
Department of Pediatrics, Division of Infectious Diseases, University of California San Diego, La Jolla, USA.
Grant R
GR
Campbell
Jennifer D
JD
Watkins
Erwann P
EP
Loret
Stephen A
SA
Spector
D000818:Animals; D016923:Cell Death; D015497:HIV-1 / Q000472:pathogenicity*; D006624:Hippocampus / Q000166:cytology / Q000473:pathology; D009474:Neurons / Q000821:virology*; D011485:Protein Binding; D051381:Rats; D013057:Spectrum Analysis; D015032:Zinc / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000633:toxicity*
D054322:tat Gene Products, Human Immunodeficiency Virus; D015032:Zinc