Reliably Measuring Cognitive Change in the Era of Chronic HIV Infection and Chronic HIV-Associated Neurocognitive Disorders

AbstractHIV-associated neurocognitive disorders (HAND) is a term used to describe a variety of neurological impairments observed in HIV-infected individuals. The pathogenic mechanisms of HAND and of its connection to HIV infection remain unknown, but one of the considered hypotheses suggests that HIV infection accelerates the development of Alzheimer’s disease. Previous studies suggested that HIV-1 Nef may contribute to HAND by inhibiting cholesterol efflux, increasing the abundance of lipid rafts, and affecting their functionality. Our comparative analysis of postmortem brain samples demonstrated a trend toward the decreased abundance of cholesterol transporter ABCA1 in samples from HIV-infected ART-treated individuals relative to samples from uninfected controls, and a reverse correlation between ABCA1 and flotillin 1, a marker for lipid rafts, in all analyzed samples. The brain samples from HIV-infected individuals, both with and without HAND, were characterized by the increased abundance of p-Tau217 peptide, which correlated with the abundance of flotillin 1. HIV-1 Nef was analyzed in samples from HAND-affected individuals by Western blot with 4 different antibodies and by LC–MS/MS, producing a Nef-positivity score. A significant correlation was found between this score and the abundance of flotillin 1, the abundance of p-Tau217, and the severity of HAND. These results highlight the contribution of Nef and Nef-dependent impairment of cholesterol efflux to HAND pathogenesis and support a connection between the pathogenesis of HAND and Alzheimer’s disease.

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HIV-Associated Neurocognitive Disorders: A Global Perspective

Journal of the International Neuropsychological Society ◽

10.1017/s1355617717001102 ◽

2017 ◽

Vol 23 (9-10) ◽

pp. 860-869 ◽

Cited By ~ 28

Author(s):

Rowan Saloner ◽

Lucette A. Cysique

Keyword(s):

Hiv Infection ◽

Biomarker Discovery ◽

Longitudinal Design ◽

Neurocognitive Disorders ◽

Global Perspective ◽

Global Studies ◽

Cross Sectional ◽

Asymptomatic Neurocognitive Impairment ◽

The Rich ◽

Hiv Associated Neurocognitive Disorders

AbstractThe present review on HIV-associated neurocognitive disorders (HAND) provides a worldwide overview of studies that have investigated the rate and neuropsychological (NP) profile of HAND research since the inception of the 2007 HAND diagnostic nomenclature. In the first part, the review highlights some of the current controversies around HAND prevalence rates. In the second part, the review critically assesses some solutions to move the field forward. In the third part, we present the cross-sectional NP profile in non-Western HIV+ cohorts and in relation to Western cohorts’ findings. The adopted global perspective highlights the successful expansion of NP studies in HIV infection to culturally diverse low- to medium-income countries with high HIV burden. These studies have produced interestingly similar rates of HAND whether patients were naïve or treated and/or virally suppressed compared to the rich income countries where the NP research in NeuroHIV has originated. The perspective also demonstrates that globally, the group which is the most representative of the HIV epidemic, and thus at risk for HAND are persons with chronic HIV infection and survivors of past immunosuppression, while in relative terms, those who have been treated early with long-term viral suppression represent a minority. In the last part, we present a review of the naturalistic longitudinal NP global studies in HIV+cohorts, discuss the role of longitudinal design in solving issues around the question of asymptomatic neurocognitive impairment, and the question of biomarker discovery. Finally, we conclude by calling for greater methods and data harmonization at a global level. (JINS, 2017,23, 860–869)

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Neurocognitive profile of patients with early stages of HIV infection

European Psychiatry ◽

10.1016/j.eurpsy.2017.01.642 ◽

2017 ◽

Vol 41 (S1) ◽

pp. s505-s506

Author(s):

P. Garcia ◽

D. Hernandez ◽

C. Fillizola ◽

J.M. Santacruz ◽

H. Santamaría García

Keyword(s):

Hiv Infection ◽

Neurocognitive Disorders ◽

Aids Dementia Complex ◽

Control Group ◽

Hiv Patients ◽

Metabolic Encephalopathy ◽

Early Stages ◽

Neurocognitive Profile ◽

Cognitive Alterations ◽

Hiv Associated Neurocognitive Disorders

HIV-associated neurocognitive disorders (HAND) may include neurological disorders of various severities such as AIDS dementia complex (ADC) also known as HIV dementia and HIV-associated dementia (HAD), HIV encephalopathy, and Mild Neurocognitive Disorder (MND). As it seems HIV-associated neurocognitive disorders are associated with a metabolic encephalopathy induced by HIV infection and fueled by immune activation of macrophages and microglia. Despite of a group, evidences have described presence of cognitive alterations in HIV patients at different stages of HIV infection so far; little is known about the neurocognitive state of patients at very early stages of HIV infection. Here, we explored the neurocognitive profile of a group of cases of HIV patients at very early stages of HIV infection. We have analyzed of three groups of subjects, thus, we have studied a group of patients with early HIV infection, a healthy control group and a group of patients with mild cognitive impairment due to neurodegenerative causes. Our results suggested that cognitive processes are sensitive to very early neuropathological changes in HIV infection. Noteworthy, our results also showed that neurocognitive profile of HIV patients differs from those cognitive alterations in patients with mild cognitive disorders associated to primary neurodegeneration. Together, our results point out that HIV infection generates neural changes even at early stages of infection. Furthermore, our results highlight the importance of a deep neurocognitive exploration at very early stages of HIV infection as this approach allow improve the accompaniment, clinical attachment and interventions.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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Induction of Heme Oxygenase-1 Deficiency and Associated Glutamate-Mediated Neurotoxicity Is a Highly Conserved HIV Phenotype of Chronic Macrophage Infection That Is Resistant to Antiretroviral Therapy

Journal of Virology ◽

10.1128/jvi.01495-15 ◽

2015 ◽

Vol 89 (20) ◽

pp. 10656-10667 ◽

Cited By ~ 15

Author(s):

Alexander J. Gill ◽

Colleen E. Kovacsics ◽

Patricia J. Vance ◽

Ronald G. Collman ◽

Dennis L. Kolson

Keyword(s):

Antiretroviral Therapy ◽

Hiv Infection ◽

Heme Oxygenase ◽

Neurocognitive Disorders ◽

Heme Oxygenase 1 ◽

Type I ◽

Hiv Replication ◽

Glutamate Production ◽

Hiv 1 ◽

Hiv Associated Neurocognitive Disorders

ABSTRACTExpression of the cytoprotective enzyme heme oxygenase-1 (HO-1) is significantly reduced in the brain prefrontal cortex of HIV-positive individuals with HIV-associated neurocognitive disorders (HAND). Furthermore, this HO-1 deficiency correlates with brain viral load, markers of macrophage activation, and type I interferon responses.In vitro, HIV replication in monocyte-derived macrophages (MDM) selectively reduces HO-1 protein and RNA expression and induces production of neurotoxic levels of glutamate; correction of this HO-1 deficiency reduces neurotoxic glutamate production without an effect on HIV replication. We now demonstrate that macrophage HO-1 deficiency, and the associated neurotoxin production, is a conserved feature of infection with macrophage-tropic HIV-1 strains that correlates closely with the extent of replication, and this feature extends to HIV-2 infection. We further demonstrate that this HO-1 deficiency does not depend specifically upon the HIV-1 accessory genesnef,vpr, orvpubut rather on HIV replication, even when markedly limited. Finally, antiretroviral therapy (ART) applied to MDM after HIV infection is established does not prevent HO-1 loss or the associated neurotoxin production. This work defines a predictable relationship between HIV replication, HO-1 loss, and neurotoxin production in MDM that likely reflects processes in place in the HIV-infected brains of individuals receiving ART. It further suggests that correcting this HO-1 deficiency in HIV-infected MDM could provide neuroprotection above that provided by current ART or proposed antiviral therapies directed at limiting Nef, Vpr, or Vpu functions. The ability of HIV-2 to reduce HO-1 expression suggests that this is a conserved phenotype among macrophage-tropic human immunodeficiency viruses that could contribute to neuropathogenesis.IMPORTANCEThe continued prevalence of HIV-associated neurocognitive disorders (HAND) underscores the need for adjunctive therapy that targets the neuropathological processes that persist in antiretroviral therapy (ART)-treated HIV-infected individuals. To this end, we previously identified one such possible process, a deficiency of the antioxidative and anti-inflammatory enzyme heme oxygenase-1 (HO-1) in the brains of individuals with HAND. In the present study, our findings suggest that the HO-1 deficiency associated with excess glutamate production and neurotoxicity in HIV-infected macrophages is a highly conserved phenotype of macrophage-tropic HIV strains and that this phenotype can persist in the macrophage compartment in the presence of ART. This suggests a plausible mechanism by which HIV infection of brain macrophages in ART-treated individuals could exacerbate oxidative stress and glutamate-induced neuronal injury, each of which is associated with neurocognitive dysfunction in infected individuals. Thus, therapies that rescue the HO-1 deficiency in HIV-infected individuals could provide additional neuroprotection to ART.

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