HIV-1 Proteins, Tat and gp120, Target the Developing Dopamine System

Abstract

In 2014, 3.2 million children (< 15 years of age) were estimated to be living with HIV and AIDS worldwide, with the 240,000 newly infected children in the past year, i.e., another child infected approximately every two minutes [1]. The primary mode of HIV infection is through mother-to-child transmission (MTCT), occurring either in utero, intrapartum, or during breastfeeding. The effects of HIV-1 on the central nervous system (CNS) are putatively accepted to be mediated, in part, via viral proteins, such as Tat and gp120. The current review focuses on the targets of HIV-1 proteins during the development of the dopamine (DA) system, which appears to be specifically susceptible in HIV-1-infected children. Collectively, the data suggest that the DA system is a clinically relevant target in chronic HIV-1 infection, is one of the major targets in pediatric HIV-1 CNS infection, and may be specifically susceptible during development. The present review discusses the development of the DA system, follows the possible targets of the HIV-1 proteins during the development of the DA system, and suggests potential therapeutic approaches. By coupling our growing understanding of the development of the CNS with the pronounced age-related differences in disease progression, new light may be shed on the neurological and neurocognitive deficits that follow HIV-1 infection.

Characterization of neuropathology in the HIV-1 transgenic rat at different ages

“…1). This was not a surprise, considering previous studies that identified behavioral problems presumed to be due to dopaminergic dysfunction in those animals (Fitting et al, 2015, Liu et al, 2009, Moran, Aksenov, 2012, Moran, Booze, 2013b, Webb et al, 2010). …”

Progression of temporal processing deficits in the HIV-1 transgenic rat

“…Clinical and preclinical studies have implicated disruptions in the development of the dopamine (DA) system as an underlying factor in neurocognitive impairments observed in pediatric HIV-14647484950. A case study of five HIV-1 seropositive children observed improved motor function and activity with administration of levodopa (L-DOPA), a DA agonist51.…”

Selective developmental alterations in The HIV-1 transgenic rat: Opportunities for diagnosis of pediatric HIV-1

“…Significant evidence has been provided for alterations in the development of the dopamine (DA) system which may also underlie early selective developmental alterations observed in the HIV-1 Tg rat (review, Fitting et al 2015). Preclinical studies in the HIV-1 Tg rat have previously implicated DA system impairments as an underlying factor in chronic neurological impairment in HIV-1 infected children (Lee et al 2014; Moran et al 2012; Moran et al 2014b; Webb et al 2010).…”

“…First, to establish the early trajectory of developmental deficits in the HIV-1 Tg rat. The HIV-1 Tg rat, which express 7 of the 9 HIV-1 genes constitutively throughout development, provides a useful model for investigating the development of neurologic impairments in pediatric AIDS (review, Fitting et al 2015; Peng et al 2010; Royal et al 2012; review, Vigorito et al 2015). Developmental assessments, including locomotor activity, cross-modal PPI, and gap-PPI were conducted prior to weaning from postnatal day (PD) 12 to PD 21.…”