Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain.

Survivors of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection frequently experience lingering neurological symptoms, including impairment in attention, concentration, speed of information processing and memory. This long-COVID cognitive syndrome shares many features with the syndrome of cancer therapy-related cognitive impairment (CRCI). Neuroinflammation, particularly microglial reactivity and consequent dysregulation of hippocampal neurogenesis and oligodendrocyte lineage cells, is central to CRCI. We hypothesized that similar cellular mechanisms may contribute to the persistent neurological symptoms associated with even mild SARS-CoV-2 respiratory infection. Here, we explored neuroinflammation caused by mild respiratory SARS-CoV-2 infection - without neuroinvasion - and effects on hippocampal neurogenesis and the oligodendroglial lineage. Using a mouse model of mild respiratory SARS-CoV-2 infection induced by intranasal SARS-CoV-2 delivery, we found white matter-selective microglial reactivity, a pattern observed in CRCI. Human brain tissue from 9 individuals with COVID-19 or SARS-CoV-2 infection exhibits the same pattern of prominent white matter-selective microglial reactivity. In mice, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7-weeks post-infection; among the chemokines demonstrating persistent elevation is CCL11, which is associated with impairments in neurogenesis and cognitive function. Humans experiencing long-COVID with cognitive symptoms (48 subjects) similarly demonstrate elevated CCL11 levels compared to those with long-COVID who lack cognitive symptoms (15 subjects). Impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss in subcortical white matter were evident at 1 week, and persisted until at least 7 weeks, following mild respiratory SARS-CoV-2 infection in mice. Taken together, the findings presented here illustrate striking similarities between neuropathophysiology after cancer therapy and after SARS-CoV-2 infection, and elucidate cellular deficits that may contribute to lasting neurological symptoms following even mild SARS-CoV-2 infection.

Human immunodeficiency virus-associated neurocognitive disorders: Mind the gap.

Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HANDs) remain among the most common disorders in people infected with HIV, even in an era when potent antiretroviral therapy is widely deployed. This review discusses the clinical features of HANDs and the implications for more effective treatment. With the improved survival of individuals treated with antiretrovirals, comorbid conditions are increasingly salient, including particularly coinfection with hepatitis C and the effects of aging. This review attempts to answer why there appears to be a therapeutic gap between the salutary effects of antiretroviral regimens and normalization of neurological function. A second gap is found in the understanding of the pathophysiology of HANDs. This review addresses this and discusses the animal models that have helped to elucidate these mechanisms. Although triggered by productive HIV infection of brain macrophages, aberrant and sustained immune activation appears to play a major role in inducing HANDs, and may explain the often incomplete neurological response to highly active antiretroviral therapy. Novel therapies aimed at persistent central nervous system inflammation will be needed to close this gap.

Interleukin-17 in transverse myelitis and multiple sclerosis.

CSF IL-6 is elevated in transverse myelitis (TM) and predicts disability. Since IL-17 regulates cytokines (TNFalpha, IL-1beta and IL-6) known to stimulate IL-6 production by astrocytes, we sought to determine whether IL-17 was increased in TM and MS compared to healthy controls (HC) and other neurologic diseases (OND). IL-17 and IL-6 levels were measured in stimulated peripheral blood mononuclear cell (PBMC) supernatants from HC, MS, TM and OND. IL-17 was increased in TM compared to HC, MS, and OND (mean pg/ml+/-standard error; HC: 36.1+/-11.7, MS: 89.4+/-23.3, TM: 302.6+/-152.5, OND: 41.2+/-13.0, p=0.01). IL-6 was increased in TM relative to MS and HC (HC: 2624 pg/ml+/-641, MS: 6129+/-982, TM: 12,536+/-2657, OND: 6920+/-1801, p<0.002). MS patients with early disease (<2 years) also had increased levels of IL-17 (p<0.04) and IL-6 (p<0.05). Cytokine neutralization experiments demonstrated that IL-6 was the main inducer of astrocyte IL-6 production. We conclude that IL-17 and IL-6 production from PBMC in TM and early MS are increased and induce astrocyte IL-6 production through IL-6.

HIV-1 Tat-coated nanoparticles result in enhanced humoral immune responses and neutralizing antibodies compared to alum adjuvant.

HIV-1 Tat has been identified as an attractive target for vaccine development and is currently under investigation in clinical trials as both a therapeutic and preventative vaccine for HIV-1. It is well known that protein based vaccines produce poor immune responses by themselves and therefore require adjuvants to enhance immune responses. We have previously reported on the use of anionic nanoparticles (NPs) for enhancing cellular and humoral immune responses to Tat (1-72). The purpose of this study was to further evaluate the immune response of HIV-1 Tat (1-72) coated on anionic nanoparticles compared to alum using various doses of Tat (1-72). Nanoparticles were effective at generating comparable antibody titers at both 1 and 5 microg doses of Tat (1-72), whereas the antibody titers significantly decreased at the lower dose of Tat (1-72) using alum. Anti-sera from Tat (1-72) immunized mice reacted greatest to the N-terminal and basic regions of Tat, with the NP groups showing stronger reactivity to these regions compared to alum. Moreover, the anti-sera from all Tat (1-72) immunized groups contained Tat-neutralizing antibodies and were able to significantly inhibit Tat-mediated long terminal repeat (LTR) transactivation.

Neurological complications of HIV infection.

Cognitive disorders, vacuolar myelopathy, and sensory neuropathies associated with HIV are the most common disorders in patients with HIV AIDS, and are the focus of this review. These disorders are treatable and of those associated with HIV AIDS the pathogenic mechanisms are the most understood. Although triggered by productive HIV macrophage infections, aberrant immune activation plays a major role in inducing the CNS disorders. Novel therapies aimed at these inflammatory mechanisms can be effective. The sensory neuropathies associated with HIV infection are a major cause of morbidity; incidence may be increased by the toxic effects of specific antiretroviral drugs within the peripheral nervous system.

Human immunodeficiency virus type 1 tat-mediated cytotoxicity of human brain microvascular endothelial cells.

Human immunodeficiency virus (HIV)-1 infection is often complicated with neurologic disorders, but the pathogenesis of HIV-1 encephalopathy is incompletely understood. Tat (HIV-1 transactivator protein) is released from HIV-1-infected cells and has been detected in the sera and cerebrospinal fluid of HIV-1-infected patients. Tat, along with increased inflammatory cytokines such as interferon-gamma (IFN-gamma), have been implicated in the pathogenesis of HIV-1-associated blood-brain barrier dysfunction. The present study examined the effects of Tat and IFN-gamma on human brain microvascular endothelial cells (HBMECs), which constitute the blood-brain barrier. Tat produced cytotoxicity of HBMECs, but required IFN-gamma. IFN-gamma treatment of HBMECs up-regulates vascular endothelial growth factor receptor-2 (VEGFR2/KDR), which is known to be the receptor for Tat. Tat activated KDR in the presence of IFN-gamma, and Tat-mediated cytopathic changes involve its interaction with KDR and phosphatidylinositol 3-kinase (PI3K). Further understanding and characterization of Tat-HBMEC interactions should help us understand HIV-1 neuropathogenesis and develop strategies to prevent HIV-1 encephalopathy.

Human immunodeficiency virus-associated dementia: an evolving disease.

This article reviews the changing epidemiology of HIV-associated dementia, current concepts of the different patterns of dementia under the influence of highly active antiretroviral therapy, and reviews therapeutic aspects.

Neuroprotective therapy for HIV dementia.

Despite the development and use of effective antiretroviral therapy, HIV dementia persists and has important socio-economic consequences. Significant progress has been made in our current understanding of the neuropathogenesis of HIV infection, and it is clear that adjunctive neuroprotective therapy in addition to antiretroviral therapy are necessary for prevention and treatment of this entity. In this manuscript, we discuss the rationale and the pathophysiological mechanisms that support the development of neuroprotective therapy for HIV dementia. We review all the placebo controlled clinical trials conducted to date with neuromodulatory/neuroprotective therapy in patients with HIV dementia and discuss their outcomes. We also provide a thorough review of potential new treatments for HIV dementia based on the experimental literature. We hope that this manuscript will serve as an important guide for future approaches for clinical trials and drug development for patients with HIV dementia.

Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease.

Neurogenesis occurs in the adult mammalian brain and may play roles in learning and memory processes and recovery from injury, suggesting that abnormalities in neural progenitor cells (NPC) might contribute to the pathogenesis of disorders of learning and memory in humans. The objectives of this study were to determine whether NPC proliferation, survival and neuronal differentiation are impaired in a transgenic mouse model of Alzheimer's disease (AD), and to determine the effects of the pathogenic form of amyloid beta-peptide (Abeta) on the survival and neuronal differentiation of cultured NPC. The proliferation and survival of NPC in the dentate gyrus of the hippocampus was reduced in mice transgenic for a mutated form of amyloid precursor protein that causes early onset familial AD. Abeta impaired the proliferation and neuronal differentiation of cultured human and rodent NPC, and promoted apoptosis of neuron-restricted NPC by a mechanism involving dysregulation of cellular calcium homeostasis and the activation of calpains and caspases. Adverse effects of Abeta on NPC may contribute to the depletion of neurons and cognitive impairment in AD.

Human immunodeficiency virus-1 Tat protein and methamphetamine interact synergistically to impair striatal dopaminergic function.

The human immunodeficiency virus (HIV)-1 transactivating protein Tat may be pathogenically relevant in HIV-1-induced neuronal injury. The abuse of methamphetamine (MA), which is associated with behaviors that may transmit HIV-1, may damage dopaminergic afferents to the striatum. Since Tat and MA share common mechanisms of injury, we examined whether co-exposure to these toxins would lead to enhanced dopaminergic toxicity. Animals were treated with either saline, a threshold dose of MA, a threshold concentration of Tat injected directly into the striatum, or striatal injections of Tat followed by exposure to MA. Threshold was defined as the highest concentration of toxin that would not result in a significant loss of striatal dopamine levels. One week later, MA-treated animals demonstrated a 7% decline in striatal dopamine levels while Tat-treated animals showed an 8% reduction. Exposure to both MA + Tat caused an almost 65% reduction in striatal dopamine. This same treatment caused a 56% reduction in the binding capacity to the dopamine transporter. Using human fetal neurons, enhanced toxicity was also observed when cells were exposed to both Tat and MA. Mitochondrial membrane potential was disrupted and could be prevented by treatment with antioxidants. This study demonstrates that the HIV-1 'virotoxin' Tat enhances MA-induced striatal damage and suggests that HIV-1-infected individuals who abuse MA may be at increased risk of basal ganglia dysfunction.

Human immunodeficiency virus (HIV) proteins in neuropathogenesis of HIV dementia.

Human immunodeficiency virus (HIV) infection of the nervous system is unique when compared with other viral encephalitides. Neuronal cell loss occurs in the absence of neuronal infection. Viral proteins, termed "virotoxins," are released from the infected glial cells that initiate a cascade of positive feedback loops by activating uninfected microglial cells and astrocytes. These activated cells release a variety of toxic substances that result in neuronal dysfunction and cell loss. The virotoxins act by a hit and run phenomenon. Thus, a transient exposure to the proteins initiates the neurotoxic cascade. High concentrations of these proteins likely occur in tight extracellular spaces where they may cause direct neurotoxicity as well. The emerging concepts in viral protein-induced neurotoxicity are reviewed as are the neurotoxic potential of each protein. Future therapeutic strategies must target common mechanisms such as oxidative stress and dysregulation of intracellular calcium involved in virotoxin-mediated neurotoxicity.

Molecular basis for interactions of HIV and drugs of abuse.

In certain populations around the world, the HIV pandemic is being driven by drug-abusing populations. Mounting evidence suggests that these patient populations have accelerated and more severe neurocognitive dysfunction compared with non-drug-abusing HIV-infected populations. Because most drugs of abuse are central nervous system stimulants, it stands to reason that these drugs may synergize with neurotoxic substances released during the course of HIV infection. Clinical and laboratory evidence suggests that the dopaminergic systems are most vulnerable to such combined neurotoxicity. Identifying common mechanisms of neuronal injury is critical to developing therapeutic strategies for drug-abusing HIV-infected populations. This article reviews 1) the current evidence for neurodegeneration in the setting of combined HIV infection and use of methamphetamine, cocaine, heroin or alcohol; 2) the proposed underlying mechanisms involved in this combined neurotoxicity; and 3) future directions for research. This article also suggests therapeutic approaches based on our current understanding of the neuropathogenesis of dementia due to HIV infection and drugs of abuse.

Understanding pathogenesis and treatment of HIV dementia: a role for magnetic resonance?

HIV dementia (HIVD) is among the most common and most feared neurological complications of AIDS. In vitro studies have identified a constellation of potentially neurotoxic inflammatory and non-inflammatory pathways, one or more of which could underlie HIVD. Magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) studies can distinguish between inflammatory and non-inflammatory pathways in vivo and suggest that either or both might be active in different patients or at different times in the same patient. This could perhaps explain the variability in HIVD development, progression and response to therapy. These findings also suggest that MRI and MRS can identify patients at risk for HIVD and predict response to therapy.

Disruption of neurogenesis in the subventricular zone of adult mice, and in human cortical neuronal precursor cells in culture, by amyloid beta-peptide: implications for the pathogenesis of Alzheimer's disease.

The adult mammalian brain contains populations of stem cells that can proliferate and then differentiate into neurons or glia. The highest concentration of such neural progenitor cells (NPC) is located in the subventricular zone (SVZ) and these cells can produce new olfactory bulb and cerebral cortical neurons. NPC may provide a cellular reservoir for replacement of cells lost during normal cell turnover and after brain injury. However, neurogenesis does not compensate for neuronal loss in age-related neurodegenerative disorders such as Alzheimer's disease (AD), suggesting the possibility that impaired neurogenesis contributes to the pathogenesis of such disorders. We now report that amyloid beta-peptide (Abeta), a self-aggregating neurotoxic protein thought to cause AD, can impair neurogenesis in the SVZ/cerebral cortex of adult mice and in human cortical NPC in culture. The proliferation and migration of NPC in the SVZ of amyloid precursor protein (APP) mutant mice, and in mice receiving an intraventricular infusion of Abeta, were greatly decreased compared to control mice. Studies of NPC neurosphere cultures derived from human embryonic cerebral cortex showed that Abeta can suppress NPC proliferation and differentiation, and can induce apoptosis. The adverse effects of Abeta on neurogenesis were associated with a disruption of calcium regulation in the NPC. Our data show that Abeta can impair cortical neurogenesis, and suggest that this adverse effect of Abeta contributes to the depletion of neurons and the resulting olfactory and cognitive deficits in AD.