title: Neonatal intrahippocampal HIV-1 protein Tat(1-86) injection: neurobehavioral alterations in the absence of increased inflammatory cytokine activation.
abstract: Pediatric AIDS caused by human immunodeficiency virus type 1 (HIV-1) remains one of the leading worldwide causes of childhood morbidity and mortality. HIV-1 proteins, such as Tat and gp120, are believed to play a crucial role in the neurotoxicity of pediatric HIV-1 infection. Detrimental effects on development, behavior, and neuroanatomy follow neonatal exposure to the HIV-1 viral toxins Tat1-72 and gp120. The present study investigated the neurobehavioral effects induced by the HIV-1 neurotoxic protein Tat1-86, which encodes the first and second exons of the Tat protein. In addition, the potential effects of HIV-1 toxic proteins Tat1-86 and gp120 on inflammatory pathways were examined in neonatal brains. Vehicle, 25 μg Tat1-86 or 100 ng gp120 was injected into the hippocampus of male Sprague-Dawley pups on postnatal day 1 (PD1). Tat1-86 induced developmental neurotoxic effects, as witnessed by delays in eye opening, delays in early reflex development and alterations in prepulse inhibition (PPI) and between-session habituation of locomotor activity. Overall, the neurotoxic profile of Tat1-86 appeared more profound in the developing nervous system in vivo relative to that seen with the first exon encoded Tat1-72 (Fitting et al., 2008b), as noted on measures of eye opening, righting reflex, and PPI. Neither the direct PD1 CNS injection of the viral HIV-1 protein variant Tat1-86, nor the HIV-1 envelope protein gp120, at doses sufficient to induce neurotoxicity, necessarily induced significant expression of the inflammatory cytokine IL-1β or inflammatory factors NF-κβ and I-κβ. The findings agree well with clinical observations that indicate delays in developmental milestones of pediatric HIV-1 patients, and suggest that activation of inflammatory pathways is not an obligatory response to viral protein-induced neurotoxicity that is detectable with behavioral assessments. Moreover, the amino acids encoded by the second tat exon may have unique actions on the developing hippocampus.
authors.affiliation: University of South Carolina, Behavioral Neuroscience Program, Department of Psychology, Columbia, SC 29208, USA.
authors.forename: Landhing M
authors.initials: LM
authors.lastname: Moran
authors.affiliation: University of South Carolina, Behavioral Neuroscience Program, Department of Psychology, Columbia, SC 29208, USA.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Fitting
authors.affiliation: University of South Carolina, Behavioral Neuroscience Program, Department of Psychology, Columbia, SC 29208, USA.
authors.forename: Rosemarie M
authors.initials: RM
authors.lastname: Booze
authors.affiliation: University of South Carolina, Behavioral Neuroscience Program, Department of Psychology, Columbia, SC 29208, USA.
authors.forename: Katy M
authors.initials: KM
authors.lastname: Webb
authors.affiliation: University of South Carolina, Behavioral Neuroscience Program, Department of Psychology, Columbia, SC 29208, USA. Electronic address: mactutus@mailbox.sc.edu.
authors.forename: Charles F
authors.initials: CF
authors.lastname: Mactutus
mesh_terms: D000367:Age Factors; D026921:Amino Acid Transport Systems, Neutral / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D002658:Developmental Disabilities / Q000139:chemically induced* / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005260:Female; D015699:HIV Envelope Protein gp120 / Q000633:toxicity; D006624:Hippocampus / Q000187:drug effects*; D006801:Humans; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009949:Orientation / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D057897:Reflex, Righting / Q000187:drug effects; D055139:Sensory Gating / Q000187:drug effects
chemical_list: D026921:Amino Acid Transport Systems, Neutral; D016207:Cytokines; D015699:HIV Envelope Protein gp120; C498964:SLC16A10 protein, human; C514793:gp120 protein, Human immunodeficiency virus 1
keywords: Cytokines; Developmental delay; HIV-1; Neurotoxicity; Tat(1–86); gp120