The blood-brain barrier (BBB) is a diffusion barrier that has an important role in maintaining a precisely regulated microenvironment protecting the neural tissue from infectious agents and toxins in the circulating system. Compromised BBB integrity plays a major role in the pathogenesis of retroviral associated neurological diseases. Human Immunodeficiency Virus (HIV) infection in the Central Nervous System (CNS) is an early event even before the serodiagnosis for HIV positivity or the initiation of antiretroviral therapy (ART), resulting in neurological complications in many of the infected patients. Macrophages, microglia and astrocytes (in low levels) are the most productively/latently infected cell types within the CNS. In this brief review, we have discussed about the effect of HIV infection and viral proteins on the integrity and function of BBB, which may contribute to the progression of HIV associated neurocognitive disorders.

As the threat of Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS) persists to rise, effective drug treatments are required to treat the infected people. Even though combination antiretroviral therapy (cART) provides stable viral suppression, it is not devoid of undesirable side effects, especially in persons undergoing long-term treatment. The present therapy finds its limitations in the emergence of multidrug resistance and accordingly finding new drugs and novel targets is the need of the hour to treat the infected persons and further to attack HIV reservoirs in the body like brain, lymph nodes to achieve the ultimate goal of complete eradication of HIV and AIDS. Natural products such as plant-originated compounds and plant extracts have enormous potential to become drug leads with anti-HIV and neuroprotective activity. Accordingly, many research groups are exploring the biodiversity of the plant kingdom to find new and better anti-HIV drugs with novel mechanisms of action and for HIV-associated neurocognitive disorders (HAND). The basic challenge that still persists is to develop viral replication-targeted therapy using novel anti-HIV compounds with new mode of action, accepted toxicity and less resistance profile. Against this backdrop, the World Health Organization (WHO) suggested the need to evaluate ethno-medicines for the management of HIV/AIDS. Consequently, there is need to evaluate traditional medicine, particularly medicinal plants and other natural products that may yield effective and affordable therapeutic agents. Although there are a good number of reports on traditional uses of plants to treat various diseases, knowledge of herbal remedies used to manage HIV/AIDS and HAND are scanty, vague and not well documented. In this review, plant substances showing a promising action that is anti-HIV and HAND will be explored along with what they interact. Since some plant substances are also known to modulate several cellular factors which are also involved in the replication of HIV and hence their role as potential candidates will be discussed. HIV/AIDS being an exceptional epidemic, demands an exceptional approach and that forms very much focus for the current review.

Alzheimer’s disease (AD) is characterized by progressive dysfunction of memory and higher cognitive functions with abnormal accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles throughout cortical and limbic brain regions. At present no curative treatment is available, and research focuses on drugs for slowing disease progression or providing prophylaxis. Withania somnifera (WS) also known as ‘ashwagandha’ is used widely in Ayurvedic medicine as a nerve tonic and memory enhancer. However, there is a paucity of data on the potential neuroprotective effects of W.somnifera against β-Amyloid (1–42)-induced neuropathogenesis. In the present study, we have tested the neuroprotective effects of methanol:Chloroform (3:1) extract of ashwagandha against β-amyloid induced toxicity and HIV-1Ba-L (clade B) infection using a human neuronal SK-N-MC cell line. Our results showed that β-amyloid induced cytotoxic effects in SK-N-MC cells as shown by decreased cell growth when tested individually. Also, confocal microscopic analysis showed decreased spine density, loss of spines and decreased dendrite diameter, total dendrite and spine area in clade B infected SK-N-MC cells compared to uninfected cells. However, when ashwagandha was added to β-amyloid treated and HIV-1 infected samples, the toxic effects were neutralized. Further, the MTT cell viability assays and the peroxisome proliferator-activated receptor-γ (PPARγ) levels supported these observations indicating the neuroprotective effect of WS root extract against β-amyloid and HIV-1Ba-L (clade B) induced neuro-pathogenesis.

BackgroundHIV-associated neurocognitive disorder (HAND) is characterized by development of cognitive, behavioral and motor abnormalities, and occurs in approximately 50% of HIV infected individuals. In the United States, the prevalence of cigarette smoking ranges from 35-70% in HIV-infected individuals compared to 20% in general population. Cognitive impairment in heavy cigarette smokers has been well reported. However, the synergistic effects of nicotine and HIV infection and the underlying mechanisms in the development of HAND are unknown.ResultsIn this study, we explored the role of nicotine in the progression of HAND using SK-N-MC, a neuronal cell line. SK-N-MC cells were infected with HIV-1 in the presence or absence of nicotine for 7 days. We observed significant increase in HIV infectivity in SK-N-MC treated with nicotine compared to untreated HIV-infected neuronal cells. HIV and nicotine synergize to significantly dysregulate the expression of synaptic plasticity genes and spine density; with a concomitant increase of HDAC2 levels in SK-N-MC cells. In addition, inhibition of HDAC2 up-regulation with the use of vorinostat resulted in HIV latency breakdown and recovery of synaptic plasticity genes expression and spine density in nicotine/HIV alone and in co-treated SK-N-MC cells. Furthermore, increased eIF2 alpha phosphorylation, which negatively regulates eukaryotic translational process, was observed in HIV alone and in co-treatment with nicotine compared to untreated control and nicotine alone treated SK-N-MC cells.ConclusionsThese results suggest that nicotine and HIV synergize to negatively regulate the synaptic plasticity gene expression and spine density and this may contribute to the increased risk of HAND in HIV infected smokers. Apart from disrupting latency, vorinostat may be a useful therapeutic to inhibit the negative regulatory effects on synaptic plasticity in HIV infected nicotine abusers.

Alzheimer's disease (AD) is characterized by progressive dysfunction of memory and higher cognitive functions with abnormal accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles throughout cortical and limbic brain regions. Withania somnifera (WS) also known as ‘ashwagandha’ (ASH) is used widely in Ayurvedic medicine as a nerve tonic and memory enhancer. However, there is paucity of data on potential neuroprotective effects of ASH against β-Amyloid (1–42) (Aβ) induced neuropathogenesis. In the present study, we have tested the neuroprotective effects of Methanol: Chloroform (3:1) extract of ASH and its constituent Withanolide A (WA) against Aβ induced toxicity, HIV-1Ba-L (clade B) infection and the effects of drugs of abuse using a human neuronal SK-N-MC cell line. Aβ when tested individually, induced cytotoxic effects in SK-N-MC cells as shown by increased trypan blue stained cells. However, when ASH was added to Aβ treated cells the toxic effects were neutralized. This observation was supported by cellular localization of Aβ, MTT formazan exocytosis, and the levels of acetylcholinesterase activity, confirming the chemopreventive or protective effects of ASH against Aβ induced toxicity. Further, the levels of MAP2 were significantly increased in cells infected with HIV-1Ba-L (clade B) as well as in cells treated with Cocaine (COC) and Methamphetamine (METH) compared with control cells. In ASH treated cells the MAP2 levels were significantly less compared to controls. Similar results were observed in combination experiments. Also, WA, a purified constituent of ASH, showed same pattern using MTT assay as a parameter. These results suggests that neuroprotective properties of ASH observed in the present study may provide some explanation for the ethnopharmacological uses of ASH in traditional medicine for cognitive and other HIV associated neurodegenerative disorders and further ASH could be a potential novel drug to reduce the brain amyloid burden and/or improve the HIV-1 associated neurocognitive impairments