Abstract
BackgroundHIV-infected individuals are at an increased risk of developing neurological abnormalities. HIV induces neurotoxicity by host cellular factors and individual viral proteins. Some of these proteins including viral protein R (Vpr) promote immune activation and neuronal damage. Vpr is known to contribute to cell death of cultured rat hippocampal neurons and suppresses axonal growth. Behavioral studies are limited and suggest hyperactivity in the presence of Vpr. Thus Vpr may play a role in hippocampal loss of function. The purpose of this study is to determine the ability of HIV-1 Vpr production by astrocytes in the hippocampus to cause neurological deficits and memory impairments.MethodsWe tested the performance of rats in novel object and novel location tasks after hippocampal infusion with astrocytes expressing HIV-1 Vpr. Synaptic injury and morphological changes were measured by synaptophysin immunoreactivity and Nissl staining.ResultsVpr-infused rats showed impaired novel location and novel object recognition compared with control rats expressing green fluorescent protein (GFP). This impairment was correlated with a significant decrease in synaptophysin immunoreactivity in the hippocampal CA3 region, suggesting synaptic injury in HIV-1 Vpr-treated animals. In addition, Nissl staining showed morphological changes indicative of neuronal chromatolysis in the Vpr group. The Vpr-induced neuronal damage and synaptic loss suggest that neuronal dysfunction caused the spatial and recognition memory deficits found in the Vpr-infused animals.ConclusionsIn this study, we demonstrate that HIV-1 Vpr produced by astrocytes in the hippocampus impairs hippocampal-dependent learning. The data suggest Vpr is a neurotoxin with the potential to cause learning impairment in HIV-1 infected individuals even under conditions of limited viral replication.
Highlights
The impact of HIV-1 has been moderated by the use of combination antiretroviral therapy that converts the infection from a once certain death sentence to a serious, but treatable chronic illness [1,2]
viral protein R (Vpr) expression from brain monocytes in a transgenic mouse showed synaptic injury and disruption of neurotransmitter homeostatic enzymes as well as hyperexcitability and aberrant motor activity [28]. While these findings indicate that Vpr can alter central nervous system (CNS) function, it is unknown whether Vpr expressed by astrocytes contributes to neurocognitive impairments
Since deletion of the major presynaptic terminal protein, synaptophysin, produces impairment in tests of object novelty and spatial learning in mice [54], we examined whether infusion of the Vpr-expressing astrocytes affected synaptophysin expression in the hippocampus
Summary
The impact of HIV-1 has been moderated by the use of combination antiretroviral therapy (cART) that converts the infection from a once certain death sentence to a serious, but treatable chronic illness [1,2]. The mechanisms that mediate ongoing neurocognitive impairments in patients on suppressive cART remain an active area of study [7,8]. In patients on suppressive cART with undetectable plasma and cerebrospinal fluid (CSF) viremia, even low levels of viral activity in astrocytes may provide a source for viral neurotoxins. Astrocytic infection is best characterized by limited production of early HIV-1 gene products [17,18,19], there are reports supporting very low levels of replication after initial infection or by reduction of a number of host cell restriction factors [12,20,21,22]. HIV induces neurotoxicity by host cellular factors and individual viral proteins Some of these proteins including viral protein R (Vpr) promote immune activation and neuronal damage. The purpose of this study is to determine the ability of HIV-1 Vpr production by astrocytes in the hippocampus to cause neurological deficits and memory impairments
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