Human immunodeficiency virus type 1 gp120 inhibits long-term potentiation via chemokine receptor CXCR4 in rat hippocampal slices.
Human immunodeficiency virus type 1 (HIV-1) infection in its human host often results in progressive dementia and encephalopathy in adults and children, respectively. The mechanisms underlying virus-induced neurocognitive dysfunction are not fully understood. However, several studies strongly suggest that secretory viral and immune products from infected brain macrophages and microglia affect the onset and tempo of disease. One critical neurotoxin among these secretory products is the HIV-1 envelope glycoprotein gp120. To better understand how HIV-1 gp120 may affect cognitive function, we studied its effects on long-term potentiation (LTP) in the CA1 region of rat hippocampus, the brain region best linked to learning and memory. Although no effects were observed on basal synaptic transmission, HIV-1 gp120 inhibited LTP in a concentration-dependent manner in the presence of gamma-aminobutyric acid type A (GABAA) receptor antagonist. Heat-inactivated gp120 failed to block LTP. The HIV-1 gp120-mediated LTP inhibition was blocked by T140, a chemokine receptor CXCR4 antagonist, demonstrating gp120 inhibition of LTP via CXCR4. HIV-1 gp120 V3 loop peptides mimicked the inhibitory effects of HIV-1 gp120 protein on LTP. Monoclonal antibodies against the V3 loop epitope KRIHI eliminated the HIV-1 gp120 effects on LTP. These results further underscore the importance of HIV-1 gp120 in the pathogenesis of HIV-1-associated cognitive impairments seen during progressive viral infection.
Dong
Jun
J
The Laboratory of Neurophysiology at Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 68198-5880, USA.
Xiong
Huangui
H
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D013997:Time Factors
D000906:Antibodies; C486264:Cxcr4 protein, rat; D015699:HIV Envelope Protein gp120; D009842:Oligopeptides; D010446:Peptide Fragments; D019718:Receptors, CXCR4; C116977:T140 peptide