HIV-1 Tat protein increases microglial outward K(+) current and resultant neurotoxic activity.

Microglia plays a crucial role in the pathogenesis of HIV-1-associated neurocognitive disorders. Increasing evidence indicates the voltage-gated potassium (Kv) channels are involved in the regulation of microglia function, prompting us to hypothesize Kv channels may also be involved in microglia-mediated neurotoxic activity in HIV-1-infected brain. To test this hypothesis, we investigated the involvement of Kv channels in the response of microglia to HIV-1 Tat protein. Treatment of rat microglia with HIV-1 Tat protein (200 ng/ml) resulted in pro-inflammatory microglial activation, as indicated by increases in TNF-α, IL-1ß, reactive oxygen species, and nitric oxide, which were accompanied by enhanced outward K(+) current and Kv1.3 channel expression. Suppression of microglial Kv1.3 channel activity, either with Kv1.3 channel blockers Margatoxin, 5-(4-Phenoxybutoxy)psoralen, or broad-spectrum K(+) channel blocker 4-Aminopyridine, or by knockdown of Kv1.3 expression via transfection of microglia with Kv1.3 siRNA, was found to abrogate the neurotoxic activity of microglia resulting from HIV-1 Tat exposure. Furthermore, HIV-1 Tat-induced neuronal apoptosis was attenuated with the application of supernatant collected from K(+) channel blocker-treated microglia. Lastly, the intracellular signaling pathways associated with Kv1.3 were investigated and enhancement of microglial Kv1.3 was found to correspond with an increase in Erk1/2 mitogen-activated protein kinase activation. These data suggest targeting microglial Kv1.3 channels may be a potential new avenue of therapy for inflammation-mediated neurological disorders.

4-Aminopyridine improves spatial memory in a murine model of HIV-1 encephalitis.

HIV-1-associated neurocognitive disorders (HAND) remains a significant source of morbidity in the era of wide spread use of highly active antiretroviral therapy. Disease is precipitated by low levels of viral growth and glial immune activation within the central nervous system. Blood borne macrophage and microglia affect a proinflammatory response and release viral proteins that affects neuronal viability and leads to death of nerve cells. Increasing evidence supports the notion that HAND is functional channelopathy, but proof of this concept remains incomplete. Based on their role in learning and memory processes, we now posit that voltage-gated potassium (K(v)) channels could be a functional substrate for disease. This was tested in the severe combined immunodeficient (SCID) mouse model of HIV-1 encephalitis (HIVE) by examining whether the K(v) channel blocker, 4-aminopyridine (4-AP), could affect behavioral, electrophysiological, and morphological measures of learning and memory. HIVE SCID mice showed impaired spatial memory in radial arm water maze tests. Electrophysiology studies revealed a reduction of long-term potentiation (LTP) in the CA1 region of the hippocampus. Importantly, systemic administration of 4-AP blocked HIV-1-associated reduction of LTP and improved animal performance in the radial arm water maze. These results support the importance of K(v) channel dysfunction in disease but, more importantly, provide a potential target for adjunctive therapies for HAND.

Methamphetamine abuse, HIV infection, and neurotoxicity.

Methamphetamine (Meth) use and human immunodeficiency virus (HIV) infection are major public health problems in the world today. Ample evidence indicates that HIV transfection risk is greatly enhanced with Meth use. Studies have shown that both HIV infection and Meth abuse can cause neuronal injury leading to neurodegeneration. While many studies have focused on the individual effects of Meth and HIV on the brain, few investigations have been carried out on their co-morbid effect in the nervous system. In this review, we try to summarize recent progress on individual effects of Meth and HIV on neurodegeneration and their potential underlying mechanisms, in addition to exploring their co-morbid effect on the brain.

Pathogenesis of Human Immunodeficiency Virus Type-1 (HIV-1)-Associated Dementia: Role of Voltage-Gated Potassium Channels.

HIV-1-associated dementia (HAD) describes the cognitive impairments and behavioral disturbances which afflict many HIV-infected individuals. Although the incidence of HAD has decreased significantly in the era of HAART, it remains a significant complication of HIV-1 infection as patients with acquired immune deficient syndrome (AIDS) live longer, antiretroviral drugs remain unable to effectively cross the blood-brain barrier (BBB), and HIV-1 resistance grows due to viral strain mutation. Although the precise mechanism leading to HAD is incompletely understood, it is commonly accepted its progression involves a critical mass of infected and activated mononuclear phagocytes (MP; brain perivascular macrophages and microglia) releasing immune and viral products in brain. These cellular and viral products induce neuronal dysfunction and injury via various signaling pathways. Emerging evidence indicates that voltage-gated potassium (K(v)) channels, key regulators of cell excitability and animal behavior (learning and memory), are involved in the pathogenesis of HAD/HAND. Here we survey the literature and find HAD related alterations in cellular and viral products can alter MP and neuronal K(v) channel activity, leading to MP and neuronal dysfunction and cognitive deficits. Thus, MP and neuronal K(v) channels may be a new target in the effort to develop therapies for HAD and perhaps other inflammatory neurodegenerative disorders.