Brains Of HIV-infected Patients Research Articles

Extracellular vesicle-mediated amyloid transfer to neural progenitor cells: implications for RAGE and HIV infection

Amyloid beta (Aβ) deposition was demonstrated to be elevated in the brains of HIV-infected patients and associated with neurocognitive decline; however, the mechanisms of these processes are poorly understood. The goal of the current study was to address the hypothesis that Aβ can be transferred via extracellular vesicles (ECVs) from brain endothelial cells to neural progenitor cells (NPCs) and that this process can contribute to abnormal NPC differentiation. Mechanistically, we focused on the role of the receptor for advanced glycation end products (RAGE) and activation of the inflammasome in these events. ECVs loaded with Aβ (Aβ-ECVs) were readily taken up by NPCs and Aβ partly colocalized with the inflammasome markers ASC and NLRP3 in the nuclei of the recipient NPCs. This colocalization was affected by HIV and RAGE inhibition by a high-affinity specific inhibitor FPS-ZM1. Blocking RAGE resulted also in an increase in ECV number produced by brain endothelial cells, decreased Aβ content in ECVs, and diminished Aβ-ECVs transfer to NPC nuclei. Interestingly, both Aβ-ECVs and RAGE inhibition altered NPC differentiation. Overall, these data indicate that RAGE inhibition affects brain endothelial ECV release and Aβ-ECVs transfer to NPCs. These events may modulate ECV-mediated amyloid pathology in the HIV-infected brain and contribute to the development of HIV-associated neurocognitive disorders.

Lesions of brain structures in HIV infection

A feature of the HIV epidemic is currently a large number of comorbid and severe forms of the disease, with frequent involvement in the pathological process of the brain. Brain lesions can be primary, caused by the human immunodeficiency virus itself and secondary, due to the development of opportunistic and secondary diseases and tumors. Correct and timely deciphering of the nature of brain damage is necessary for the choice of treatment tactics and as a consequence of reducing mortality.
 Objective. To study the radiological manifestations of brain damage in HIV infection in urgent and planned admission of patients to specialized hospitals.
 Materials and methods of research. In the work, studies were conducted to study the clinical and radiological manifestations of brain damage in HIV-infected patients admitted to various medical institutions with a diagnosis of HIV infection. Radiation examination of the brain was performed in adult HIV-infected patients (n = 410) using magnetic resonance imaging with intravenous contrast. The final diagnosis was made taking into account clinical, laboratory, radiological studies on the classification of ICD-10 in accordance with the domestic requirements of the formulation of comorbid diagnosis.
 Conclusion. To correctly decipher the nature of brain damage, it is necessary to use comprehensive studies including clinical, laboratory and radiation examination methods. Magnetic resonance imaging with intravenous contrast is the method of choice in the examination of the brain in HIV-infected patients.
 The structure of brain damage in HIV-infected patients had a different nature: in 54.4% there were signs of the presence of opportunistic and secondary diseases; in 24.9% signs of HIV encephalopathy; in 13.2% signs of nonspecific changes in small vessels of the brain, indicating premature aging or abnormal development; in 7.56% signs of involvement of the brain in the pathological process were not detected.
 Structure and opportunistic secondary diseases were presented: toxoplasmosis of the brain 18.3%; herpes lesions 12.2%; chief of 10.24%; neuroinfection unspecified etiology is 12.2%; cryptococcosis 4.39%; TB is 2.44%; lymphoma of the brain is 2.44%; MAC infection is 0.24%.
 Brain damage in HIV-infected patients is largely characterized by synchronicity (mixed infection in 8.52 %) and multifactorial lesions.

Brain PET Imaging: Value for Understanding the Pathophysiology of HIV-associated Neurocognitive Disorder (HAND).

The purpose of this review is to summarize recent developments in PET imaging of neuropathologies underlying HIV-associated neurocognitive dysfunction (HAND). We concentrate on the recent post antiretroviral era (ART), highlighting clinical and preclinical brain PET imaging studies. In the post ART era, PET imaging has been used to better understand perturbations of glucose metabolism, neuroinflammation, the function of neurotransmitter systems, and amyloid/tau protein deposition in the brains of HIV-infected patients and HIV animal models. Preclinical and translational findings from those studies shed a new light on the complex pathophysiology underlying HAND. The molecular imaging capabilities of PET in neuro-HIV are great complements for structural imaging modalities. Recent and future PET imaging studies can improve our understanding of neuro-HIV and provide biomarkers of disease progress that could be used as surrogate endpoints in the evaluation of the effectiveness of potential neuroprotective therapies.

Case control study: magnetic resonance spectroscopy of brain in HIV infected patients.

BackgroundIn vivo proton magnetic resonance spectroscopy (1H-MRS) studies on brain in HIV infected patients have shown significant alteration in neuro-biochemicals.MethodsIn this study, we measured the neuro-biochemical metabolites from the left frontal white matter (FWM) and left basal ganglia (BG) caudate head nucleus in 71 subjects that include 30 healthy controls, 20 asymptomatic HIV and 21 HIV patients with CNS lesion. Proton MR spectra were acquired at 3 T MRI system and the concentration (institutional units) of tNAA (N-acetylaspartate, NAA + N-acetylaspartylglutamate, NAAG), tCr (Creatine, Cr + phosphocreatine, PCr), choline containing compounds (tCho), glutamate + glutamine (Glx) and lipid and macromolecules at 0.9 ppm were determined using LC Model.ResultsIn BG, the concentration of tNAA (6.71 ± 0.64) was decreased and in FWM, the concentration of Glx (20.4 ± 7.8), tCr (9.14 ± 3.04) and lipid and macromolecules at 0.9 ppm (8.69 ± 2.96) were increased in HIV patients with CNS lesion. In healthy controls, the concentration of tNAA in BG was 7.31 ± 0.47 and concentration of Glx, tCr and lipid and macromolecules in FWM were 15.0 ± 6.06, 6.95 ± 2.56, 5.59 ± 1.56, respectively.ConclusionReduced tNAA in BG suggests neuronal loss in HIV patients with CNS lesion while increased Glx in FWM may suggest excito-toxicity. In addition, increased levels of tCr in FWM of HIV patients were observed. The study indicates region specific metabolic changes in tNAA, tCr and Glx in brain of HIV infected patients.

LFA1 Mediated Attachment of Primary Human Monocytes to Activated Brain Microvascular Endothelial Cells Is Regulated by SDF-1α through the SRC Family Kinase Lyn; Potential Involvement of This Signaling Pathway in HIV-Associated Dementia.

Infiltration of activated monocytes into the brain of HIV-infected patients is a prerequisite for the development of HIV-associated dementia (HAD). The chemokine stromal derived factor-1α (SDF-1α) is expressed at increased levels in the central nervous system (CNS) of HAD patients and elicits chemotaxis and other cellular effects through its receptor CXCR4. In this project, we investigated the intracellular signaling pathway by which SDF-1α mediates the movement and attachment of monocytes to brain microvascular endothelia, and which may contribute to their infiltration into the CNS in HAD. We demonstrated that SDF-1α stimulates migration of primary human monocytes through its receptor CXCR4, and decreases monocyte adherence to surfaces coated with ICAM-1. SDF-1α also decreases monocyte adherence to brain microvascular endothelial cells (BMVEC) activated with the pro-inflammatory cytokines TNF-α or IL-1β, or with recombinant HIV-1 envelope glycoprotein (gp120), which increase endothelial cells expression of ICAM-1. The decreased monocyte adherence was linked to down regulation of the activation-dependent epitope of the β2 integrin LFA-1 which is a ligand for ICAM-1. We then demonstrated that the Src family kinase Lyn is a central modulator of migration and LFA-1-mediated adhesion of SDF-1α-stimulated primary monocytes. Using siRNA knockdown we achieved 80% down regulation of Lyn kinase in human monocytes. Lyn down regulation decreased SDF-1α-mediated migration and prevented its inhibition of monocyte attachment to ICAM-1 coated surfaces and activated BMVEC. These data indicate that in SDF-1α-stimulated primary human monocytes Lyn is a positive regulator of cell migration, and a negative regulator of cell adhesion to BMVEC by inhibiting the ICAM-1 binding activity of the LFA-1 integrin. Thus, CXCR4-triggered inside-out integrin signaling, through Lyn, inhibits adherence and stimulates movement of monocytes towards SDF-1α gradient on BMVEC monolayers. These results provide new insight into the intracellular signaling cascade that controls primary human monocytes movement and attachment at the blood brain barrier.

Tat peptides inhibit neprilysin

Dementia associated with human immunodeficiency virus (HIV) infection occurs commonly in the aging population and amyloid depositions are noted in the brains of patients with HIV infection in younger age groups. This suggests a dysregulation of amyloid processing in the setting of HIV infection. The Tat protein of HIV has been implicated in the neuropathogenesis of HIV infection due to its neurotoxic and glial activation properties. However, Tat protein and Tat-derived peptides were recently also shown to inhibit neprilysin, the major amyloid beta peptide degrading enzyme in brain, in a cell aggregate system. This effect could contribute to the observed accumulation of amyloid in the brain of HIV-infected patients. The authors report here that peptides derived from the Tat protein, but not Tat protein itself, inhibit homogeneous recombinant neprilysin. This inhibition was found to be competitive and reversible and therefore does not involve covalent bond formation. Tat peptides and Tat protein were slowly hydrolyzed by neprilysin. Thus the accumulation of Tat-derived proteolytic fragments may serve to inhibit neprilysin and increase amyloid beta peptide levels.

Molecular and cellular mechanisms of neuronal cell death in HIV dementia.

The deaths of neurons, astrocytes and endothelial cells have been described in patients with HIV (human immunodeficiency virus) dementia. HIV-1 does not infect neurons; instead, neurotoxic substances shed by infected glia and macrophages can induce a form of programmed cell death called apoptosis in neurons. These neurotoxins include the HIV-1 proteins Tat and gp120, as well as pro-inflammatory cytokines, chemokines, excitotoxins and proteases. In this article we review the evidence for apoptosis of various cell types within the brain of HIV-infected patients, and describe in vitro and in vivo experimental studies that have elucidated the mechanisms by which HIV causes apoptosis of brain cells.

Independent evolution of human immunodeficiency virus (HIV) drug resistance mutations in diverse areas of the brain in HIV-infected patients, with and without dementia, on antiretroviral treatment.

AIDS dementia complex (ADC) in human immunodeficiency virus (HIV)-infected patients continues to be a problem in the era of highly active antiretroviral therapy (HAART). A better understanding of the drug resistance mutation patterns that emerge in the central nervous system (CNS) during HAART is of paramount importance as these differences in drug resistance mutations may explain underlying reasons for poor penetration of antiretroviral drugs into the CNS and suboptimal concentrations of the drugs that may reside in the brains of HIV-infected individuals during therapy. Thus, we provide a detailed analysis of HIV type 1 (HIV-1) protease and reverse transcriptase (RT) genes derived from different regions of the brains of 20 HIV-1-infected patients (5 without ADC, 2 with probable ADC, and 13 with various stages of ADC) on antiretroviral therapy. We show the compartmentalization and independent evolution of both primary and secondary drug resistance mutations to both RT and protease inhibitors in diverse regions of the CNS of HIV-infected patients, with and without dementia, on antiretroviral therapy. Our results suggest that the independent evolution of drug resistance mutations in diverse areas of the CNS may emerge as a consequence of incomplete suppression of HIV, probably related to suboptimal drug levels in the CNS and drug selection pressure. The emergence of resistant virus in the CNS may have considerable influence on the outcome of neurologic disease and also the reseeding of HIV in the systemic circulation upon failure of therapy.

Human Immunodeficiency Virus Infection of the Brain: Pitfalls in Evaluating Infected/Affected Cell Populations

Monocyte/macrophages and CD4 T-cells are the primary hematopoietic targets of productive HIV infection. In the brain, potential cellular targets for HIV infection include perivascular and parenchymal macrophages/microglia, oligodendrocytes, endothelia, neurons, and astrocytes. We examine evidence of productive and non-productive infection for each cell type in the brains of HIV-infected patients with and without HIV encephalitis. Despite the voluminous literature and substantial experimental effort over the past two decades, evidence for productive infection of any brain cell other than macrophages is left wanting.

HIV-Tat protein induces oxidative and inflammatory pathways in brain endothelium.

Impaired function of the brain vasculature might contribute to the development of HIV-associated dementia. For example, injury or dysfunction of brain microvascular endothelial cells (BMEC) can lead to the breakdown of the blood-brain barrier (BBB) and thus allow accelerated entry of the HIV-1 virus into the CNS. Mechanisms of injury to BMEC during HIV-1 infection are not fully understood, but the viral gene product Tat may be, at least in part, responsible for this effect. Tat can be released from infected perivascular macrophages in the CNS of patients with AIDS, and thus BMEC can be directly exposed to high concentrations of this protein. To study oxidative and inflammatory mechanisms associated with Tat-induced toxicity, BMEC were exposed to increasing doses of Tat1-72, and markers of oxidative stress, as well as redox-responsive transcription factors such as nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), were measured. Tat1-72 treatment markedly increased cellular oxidative stress, decreased levels of intracellular glutathione and activated DNA binding activity and transactivation of NF-kappaB and AP-1. To determine if Tat1-72 can stimulate inflammatory responses in brain endothelium in vivo, expression of monocyte chemoattractant protein-1 (MCP-1), an NF-kappaB and AP-1-dependent chemokine, was studied in brain tissue in mice injected with Tat1-72 into the right hippocampus. Tat1-72 markedly elevated the MCP-1 mRNA levels in brain tissue. In addition, a double immunohistochemistry study revealed that MCP-1 protein was markedly overexpressed on brain vascular endothelium. These data indicate that Tat1-72 can induce redox-related inflammatory responses both in in vitro and in vivo environments. These changes can directly lead to disruption of the BBB. Thus, Tat can play an important role in the development of detrimental vascular changes in the brains of HIV-infected patients.

Herpesvirus infection of eye and brain in HIV infected patients

Objectives: To compare histological with genome detection methods for diagnosis of herpesvirus infection in eye and brain of HIV infected patients undergoing necropsy and to correlate these findings with both...

Brain imaging in AIDS.

Although central nervous system (CNS) involvement is common in the population with acquired immunodeficiency syndrome, the presenting neurologic signs and symptoms are often vague and nonfocal. This represents a significant diagnostic challenge for the primary care physician. Cross-sectional imaging now plays an important role in the diagnosis of pathologic processes involving the brain in HIV-infected patients. Involvement of the brain with atypical viruses, parasites, fungi, and neoplasms is more prevalent in AIDS patients. On identification of a brain lesion, it is the role of the imager to characterize it in an attempt to provide a limited differential diagnosis. We review the imaging findings of the pathogens that most commonly affect the brain in AIDS patients.