Neonatal intrahippocampal HIV-1 protein Tat1-86 injection: neurobehavioral alterations in the absence of increased inflammatory cytokine activation

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 Tat(1-72) and gp120. The present study investigated the neurobehavioral effects induced by the HIV-1 neurotoxic protein Tat(1-86), which encodes the first and second exons of the Tat protein. In addition, the potential effects of HIV-1 toxic proteins Tat(1-86) and gp120 on inflammatory pathways were examined in neonatal brains. Vehicle, 25 mu g Tat(1-86) or 100 ng gp 20 was injected into the hippocampus of male Sprague-Dawley pups on postnatal day 1 (PD1). Tat(1-86) 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 Tat(1-86) appeared more profound in the developing nervous system in vivo relative to that seen with the first exon encoded Tat(1-72) (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 Tat(1-86), nor the HIV-1 envelope protein gp120, at doses sufficient to induce neurotoxicity, necessarily induced significant expression of the inflammatory cytokine IL-1 beta or inflammatory factors NF-kappa beta and I-kappa beta. 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. (C) 2014 ISDN. Published by Elsevier Ltd. All rights reserved.