Human immunodeficiency virus type 1 in the central nervous system leads to decreased dopamine in different regions of postmortem human brains

Abstract

Human immunodeficiency virus type 1 (HIV-1) invades the central nervous system (CNS) shortly after infection and becomes localized in varying concentrations in different brain regions, the most vulnerable is the basal ganglia (BG). It is hypothesized that HIV-1-mediated neuropathogenesis involves degeneration of dopaminergic neurons in the substantia nigra and the loss of dopaminergic terminals in the BG, leading to deficits in the central dopaminergic activity, resulting in progressive impairment of neurocognitive and motor functions. In the era of highly active antiretroviral therapy (HAART), although the incidence of HIV-associated dementia (HAD) has decreased, the neurocognitive and neuropsychological deficits continue to persist after HAART. In this study, We investigated the impact of HIV-1 on dopaminergic activity with respect to concentrations of dopamine (DA) and homovanillic acid (HVA) in different regions of postmortem human brains of HIV-1-negative and HIV-1+ individuals and their relationship to neurocognitive impairment. We found that in HIV-1+ as well as HIV-negative cases, dopamine and HVA concentrations in ranged widely in different brain regions. In HIV-negative brain regions, the highest concentration of DA was found in putamen, caudate, substantia nigra, and the basal ganglia. In HIV-1+ cases, there was a significant decrease in DA levels in caudate nucleus, putamen, globus pallidus, and substantia nigra compared to that in HIV-negative cases. In HIV-1+ cases, a strong correlation was found between DA levels in substantia nigra and other brain regions. Concentration of HVA in HIV-negative cases was also highest in the regions containing high dopamine levels. However, no significant decrease in regional HVA levels was found in HIV-1+ cases. HIV-1 RNA load (nondetectable [ND] to log10 6.9 copies/g tissue) also ranged widely in the same brain regions of HIV-1+ cases. Interestingly, the brain regions having the highest HIV-1 RNA had the maximum decrease in DA levels. Age, gender, ethnicity, and postmortem interval were not correlated with decrease in DA levels. Profile of DA, HVA, and HIV-1 RNA levels in the brain regions of HIV-1+ individuals treated with HAART was similar to those not treated with HAART. A majority of HIV-1+ individuals had variable degrees of neurocognitive impairments, but no specific relationship was found between the regional DA content and severity of neurocognitive deficits. These findings suggest widespread deficits in dopamine in different brain regions of HIV-1-infected cases, and that these deficits may be the results of HIV-1-induced neurodegeneration in the subcortical regions of human brain.

Drugs of Abuse, Dopamine, and HIV-Associated Neurocognitive Disorders/HIV-Associated Dementia

“…HIV-1 gp41-positive microglia were most numerous in globus pallidus obtained from the brain of AIDS encephalitis patients [27]. Relatively higher levels of HIV-1 RNA were found in dopamine-rich parts of human brain samples (substantia nigra, caudate nucleus, basal ganglia, and globus pallidus) obtained at autopsy [17,28]. Overall, these data suggest that while HIV infection can generally cause brain atrophy, "dopamine-rich" areas can show proportionally more atrophy, suggesting a propensity for HIV in targeting these brain areas.…”

“…This finding was associated with a loss of nigrostriatal dopaminergic neurons, suggesting a HIV-induced neuronal damage followed by dopamine depletion. In another postmortem sample study, Kumar et al [17] found a significant decrease in dopamine levels in dopamine-rich brain regions, including caudate nucleus, putamen, globus pallidus, and substantia nigra obtained from HIV-1-positive subjects, who actually died of HIV/ AIDS with no opportunistic infection at the time of death, compared to dopamine levels observed in HIV-negative cases. In contrast, in HIV-negative cases, the highest concentration of dopamine was found in dopamine-rich areas, including putamen, caudate, substantia nigra, and the basal ganglia.…”

“…Furthermore, exposure to most drugs of abuse increases brain levels of dopamine well beyond basal levels and levels associated with "natural rewards" (e.g., food, sex) [11][12][13][14][15]. Finally, dopamine has been implicated in HIV and simian immunodeficiency virus (SIV)-induced brain pathology [16,17], and shown to promote HIV replication in macrophages [18]. The purpose of this review is to evaluate the potential role of dopamine in the development of HAND/HAD and in the exacerbation of these conditions by drugs of abuse.…”

Structural gray and white matter changes in patients with HIV

“…With regard to the caudate nucleus, neurocognitive impairment was correlated with volume reduction and reduced blood flow [35]. Furthermore, virus accumulation together with decreased dopamine levels is present within the caudate nucleus [36,37].…”

Methamphetamine Exposure Combined with HIV-1 Disease or gp120 Expression: Comparison of Learning and Executive Functions in Humans and Mice

“…Specifically, HIV-induced decreases in caudate/basal ganglia volume Kieburtz et al, 1996) and dopamine levels (Kumar et al, 2009) have been associated with poorer cognitive performance (Hestad et al, 1993;Kieburtz et al, 1996). Similarly, methamphetamine exposure causes neurotoxicity in mesolimbic and mesocortical brain regions (Mark et al, 2004).…”