scholarly journals HIV Nef and Antiretroviral Therapy Have an Inhibitory Effect on Autophagy in Human Astrocytes that May Contribute to HIV-Associated Neurocognitive Disorders

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1426
Author(s):  
Laura Cheney ◽  
Hillary Guzik ◽  
Frank P. Macaluso ◽  
Fernando Macian ◽  
Ana Maria Cuervo ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Inhibitory Effect ◽  
Neurocognitive Disorders ◽  
Autophagic Flux ◽  
People Living With Hiv ◽  
Autophagosome Formation ◽  
Human Astrocytes ◽  
Transmission Electron ◽  
Living With Hiv ◽  
Hiv Associated Neurocognitive Disorders

A significant number of people living with HIV (PLWH) develop HIV-associated neurocognitive disorders (HAND) despite highly effective antiretroviral therapy (ART). Dysregulated macroautophagy (autophagy) is implicated in HAND pathogenesis. The viral protein Nef, expressed even with suppressive ART, and certain antiretrovirals affect autophagy in non-CNS cells. Astrocytes, vital for CNS microenvironment homeostasis and neuronal health, require autophagy for their own homeostasis. We hypothesized that extracellular Nef and/or ART impact astrocyte autophagy, thus contributing to HAND. We studied in-bulk and selective autophagic flux in primary human astrocytes treated with extracellular Nef and/or a combination of tenofovir+emtricitabine+raltegravir (ART) using Western blotting, a tandem fluorescent LC3 reporter, and transmission electron microscopy/morphometry. We show that after 24 h treatment, Nef and ART decrease autophagosomes through different mechanisms. While Nef accelerates autophagosome degradation without inducing autophagosome formation, ART inhibits autophagosome formation. Combination Nef+ART further depletes autophagosomes by inducing both abnormalities. Additionally, extracellular Nef and/or ART inhibit lysosomal degradation of p62, indicating Nef and/or ART affect in-bulk and selective autophagy differently. Dysregulation of both autophagic processes is maintained after 7 days of Nef and/or ART treatment. Persistent autophagy dysregulation due to chronic Nef and/or ART exposure may ultimately result in astrocyte and neuronal dysfunction, contributing to HAND.

scholarly journals Depression and Apathy Among People Living with HIV: Implications for Treatment of HIV Associated Neurocognitive Disorders

2014 ◽  
Vol 19 (8) ◽  
pp. 1430-1437 ◽  
Author(s):  
Vaughn E. Bryant ◽  
Nicole E. Whitehead ◽  
Larry E. Burrell ◽  
Vonetta M. Dotson ◽  
Robert L. Cook ◽  
...  
Keyword(s):  
Neurocognitive Disorders ◽  
People Living With Hiv ◽  
Living With Hiv ◽  
Hiv Associated Neurocognitive Disorders

scholarly journals Prevalence and Correlates of Neurocognitive Disorders among HIV Patients on Antiretroviral Therapy at a Kenyan Hospital

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
A. G. Mugendi ◽  
M. N. Kubo ◽  
D. G. Nyamu ◽  
L. M. Mwaniki ◽  
S. K. Wahome ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Clinical Care ◽  
Neurocognitive Impairment ◽  
Neurocognitive Disorders ◽  
Cd4 Count ◽  
People Living With Hiv ◽  
Hiv Diagnosis ◽  
Cross Sectional ◽  
Asymptomatic Neurocognitive Impairment ◽  
Living With Hiv

Background. HIV-associated neurocognitive disorders (HAND) represent a spectrum of cognitive abnormalities affecting attention, concentration, learning, memory, executive function, psychomotor speed, and/or dexterity. Our objectives in this analysis are to determine the prevalence of HAND and the covariates in a Kenyan population. Methods. We conducted a cross-sectional study in a convenient sample of people living with HIV on antiretroviral therapy (ART) attending routine care visits at the Kenyatta National Hospital HIV clinic between July and August 2015. Baseline demographics were obtained using interviewer-administered questionnaires; clinical data were abstracted from patient records. Trained research clinicians determined the neurocognitive status by administration of the International HIV Dementia Scale (IHDS), the Montreal Cognitive Assessment (MOCA) scale, and the Lawton Instrumental Activities of Daily Living (IADL) scale. Cognitive impairment was defined as a score of ≤26 on the MOCA and ≤10 on the IHDS. Descriptive analysis and logistic regression to determine predictors of screening positive for HAND were done with the significance value set at <0.05. Results. We enrolled 345 participants (202 men; 143 women). The mean age of the study population was 42 years (±standard deviation (SD) 9.5). Mean duration since HIV diagnosis and mean duration on ART were 6.3 (±SD 3.7) and 5.6 years (±SD 3.4), respectively. Median CD4 count at interview was 446 cells/mm3 (interquartile range (IQR) 278–596). Eighty-eight percent of participants screened positive for HAND, of whom 87% had asymptomatic neurocognitive impairment (ANI) and minor neurocognitive disorders (MND) grouped together while 1% had HIV-associated dementia (HAD). Patients on AZT/3TC/EFV were 3.7 times more likely to have HAND (OR = 3.7, p=0.03) compared to other HAART regimens. In the adjusted analysis, women were more likely to suffer any form of HAND than men (aOR = 2.17, 95% CI: 1.02, 4.71; p=0.045), whereas more years in school and a higher CD4 count (aOR = 0.58, 95% CI: 0.38, 0.88; p=0.012), (aOR = 0.998, 95% CI 0.997, 0.999; p=0.013) conferred a lowered risk. Conclusion. Asymptomatic and mild neurocognitive impairment is prevalent among people living with HIV on treatment. Clinical care for HIV-positive patients should involve regular screening for neurocognitive disorders while prioritizing women and those with low education and/or low CD4 counts.

scholarly journals Transcriptomic and Genetic Profiling of HIV-Associated Neurocognitive Disorders

2021 ◽  
Vol 8 ◽  
Author(s):  
Daniel Ojeda-Juárez ◽  
Marcus Kaul
Keyword(s):  
Complex Disease ◽  
Small Animal ◽  
Neurocognitive Disorders ◽  
People Living With Hiv ◽  
Future Directions ◽  
Genetic Studies ◽  
Genetic Profiling ◽  
Wide Range ◽  
Living With Hiv ◽  
Hiv Associated Neurocognitive Disorders

Early in the HIV pandemic, it became evident that people living with HIV (PLWH) develop a wide range of neurological and neurocognitive complications. Even after the introduction of combination antiretroviral therapy (cART), which dramatically improved survival of PLWH, the overall number of people living with some form of HIV-associated neurocognitive disorders (HAND) seemed to remain unchanged, although the incidence of dementia declined and questions about the incidence and diagnosis of the mildest form of HAND arose. To better understand this complex disease, several transcriptomic analyses have been conducted in autopsy samples, as well as in non-human primates and small animal rodent models. However, genetic studies in the HIV field have mostly focused on the genetic makeup of the immune system. Much less is known about the genetic underpinnings of HAND. Here, we provide a summary of reported transcriptomic and epigenetic changes in HAND, as well as some of the potential genetic underpinnings that have been linked to HAND, and discuss future directions with hurdles to overcome and angles that remain to be explored.

scholarly journals Insights into the Gene Expression Profiles of Active and Restricted Red/Green-HIV+ Human Astrocytes: Implications for Shock or Lock Therapies in the Brain

2020 ◽  
Vol 94 (6) ◽  
Author(s):  
Venkata Viswanadh Edara ◽  
Anuja Ghorpade ◽  
Kathleen Borgmann
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Neurocognitive Disorders ◽  
Antiretroviral Drugs ◽  
Gene Expression Patterns ◽  
People Living With Hiv ◽  
Human Astrocytes ◽  
Living With Hiv ◽  
Hiv 1

ABSTRACT A significant number of people living with human immunodeficiency virus type 1 (HIV-1) suffer from HIV-associated neurocognitive disorders (HAND). Many previous studies investigating HIV in astrocytes as a heterogenous population have established the relevance of astrocytes to HIV-associated neuropathogenesis. However, these studies were unable to differentiate the state of infection, i.e., active or latent, or to evaluate how this affects astrocyte biology. In this study, the pseudotyped doubly labeled fluorescent reporter red/green (R/G)-HIV-1 was used to identify and enrich restricted and active populations of HIV+ astrocytes based on the viral promoter activity. Here, we report that the majority of human astrocytes restricted R/G-HIV-1 gene expression early during infection and were resistant to reactivation by vorinostat and interleukin 1β. However, actively infected astrocytes were inducible, leading to increased expression of viral proteins upon reactivation. R/G-HIV-1 infection also significantly decreased the cell proliferation and glutamate clearance ability of astrocytes, which may contribute to excitotoxicity. Moreover, transcriptome analyses to compare gene expression patterns of astrocyte harboring active versus restricted long terminal repeats (LTRs) revealed that the gene expression patterns were similar and that the active population demonstrated more widespread and robust changes. Our data suggest that harboring the HIV genome profoundly alters astrocyte biology and that strategies that keep the virus latent (e.g., block and lock) or those that reactivate the latent virus (e.g., shock and kill) would be detrimental to astrocyte function and possibly augment their contributions to HAND. IMPORTANCE More than 36 million people are living with HIV-1 worldwide, and despite antiretroviral therapy, 30 to 50% of the people living with HIV-1 suffer from mild to moderate neurocognitive disorders. HIV-1 reservoirs in the central nervous system (CNS) are challenging to address due to low penetration of antiretroviral drugs, lack of resident T cells, and permanent integration of provirus into neural cells such as microglia and astrocytes. Several studies have shown astrocyte dysfunction during HIV-1 infection. However, little is known about how HIV-1 latency affects their function. The significance of our research is in identifying that the majority of HIV+ astrocytes restrict HIV expression and were resistant to reactivation. Further, simply harboring the HIV genome profoundly altered astrocyte biology, resulting in a proinflammatory phenotype and functional changes. In this context, therapeutic strategies to reactivate or silence astrocyte HIV reservoirs, without excising proviral DNA, will likely lead to detrimental neuropathological outcomes during HIV CNS infection.

Metabolic Syndrome in HIV-patients in Antiretroviral Therapy

2020 ◽  
Vol 18 (6) ◽  
pp. 388-395
Author(s):  
Daniel Vargas-Pacherrez ◽  
Helma P. Cotrim ◽  
Leonardo Pires ◽  
Vitor Cunha ◽  
Vitor Coelho ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Antiretroviral Therapy ◽  
International Diabetes Federation ◽  
Cross Sectional Study ◽  
People Living With Hiv ◽  
Anthropometric Data ◽  
Cross Sectional ◽  
History Of ◽  
Family History Of Hypertension ◽  
Living With Hiv

Introduction: The global prevalence of metabolic syndrome (MS) among people living with HIV/AIDS varies from 20% to 33%. Objective: to estimate the prevalence of metabolic syndrome and associated factors in a group of HIV-infected patients on antiretroviral therapy. Methods: This is a cross-sectional study with HIV-infected patients from a reference center in Bahia, Brazil. We evaluated clinical, socio-demographic and anthropometric data. MS was defined according to the guidelines of International Diabetes Federation. Results: We evaluated 152 patients with mean age of 47.3±11.6 years, 59.2% male. The main comorbidities detected were diabetes (3.3%) hypertriglyceridemia (9.3%) and metabolic syndrome (MS,38.2%). Patients with MS were predominantly women (55.2% vs 31.9%; p=0.005), older [52.1 (10.4) vs 44.3 (11.3); p<0.001], and had overweight (74.1% vs 23.4%; p<0.001). After multivariate analysis MS remained associated with age (OR = 1.076; 95% CI: 1.030 – 1.125), female sex (OR = 2.452; 95% CI: 1.114 – 5.374) and family history of hypertension (OR = 3.678; 95% CI: 1.431 – 9.395). Conclusion: Almost half of the HIV-infected patients in Bahia presents with MS which seems to be driven by classical risk factors.

scholarly journals Community-based model for the delivery of antiretroviral therapy in Cambodia: a quasi-experimental study protocol

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Sovannary Tuot ◽  
Alvin Kuo Jing Teo ◽  
Kiesha Prem ◽  
Pheak Chhoun ◽  
Chamroen Pall ◽  
...  
Keyword(s):  
Experimental Study ◽  
Antiretroviral Therapy ◽  
Scale Up ◽  
Economic Evaluations ◽  
People Living With Hiv ◽  
Cad Model ◽  
Community Based ◽  
Quasi Experimental ◽  
Living With Hiv ◽  
Art Delivery

Abstract Background Multi-month dispensing (MMD) is the mainstay mechanism for clinically stable people living with HIV in Cambodia to refill antiretroviral therapy (ART) every 3-6 months. However, less frequent ART dispensing through the community-based ART delivery (CAD) model could further reduce the clients’ and health facilities’ burden. While community-based services have been recognized as an integral component of HIV response in Cambodia, their role and effectiveness in ART delivery have yet to be systematically assessed. This study aims to evaluate the CAD model’s effectiveness on the continuum of care and treatment outcomes for stable people living with HIV in Cambodia. Methods We will conduct this quasi-experimental study in 20 ART clinics across the capital city and nine provinces between May 2021 and April 2023. Study sites were purposively selected based on the availability of implementing partners, the number of people living with HIV each clinic serves, and the accessibility of the clinics. In the intervention arm, approximately 2000 stable people living with HIV will receive ART and services from the CAD model. Another 2000 stable people living with HIV in the control arm will receive MMD—a standard care model for stable people living with HIV. The primary outcomes will be retention in care, viral load suppression, and adherence to ART. The secondary endpoints will include health providers’ work burden, the model’s cost-effectiveness, quality of life, mental health, social support, stigma, and discrimination. We will compare the outcome indicators within each arm at baseline, midline, and endline using descriptive and inferential statistics. We will evaluate the differences between the intervention and control arms using the difference-in-differences method. We will perform economic evaluations to determine if the intervention is cost-effective. Discussion This study will build the evidence base for future implementation and scale-up of CAD model in Cambodia and other similar settings. Furthermore, it will strengthen engagements with community stakeholders and further improve community mobilization, a vital pillar of the Cambodian HIV response. Trial registration ClinicalTrials.gov, NCT04766710. Registered 23 February 2021, Version 1.

scholarly journals Incidence of Herpes Zoster in HIV-Infected Patients Undergoing Antiretroviral Therapy: A Systematic Review and Meta-analysis

2021 ◽  
Vol 10 (11) ◽  
pp. 2300
Author(s):  
Han-Chang Ku ◽  
Yi-Tseng Tsai ◽  
Sriyani-Padmalatha Konara-Mudiyanselage ◽  
Yi-Lin Wu ◽  
Tsung Yu ◽  
...  
Keyword(s):  
Systematic Review ◽  
Herpes Zoster ◽  
Antiretroviral Therapy ◽  
Random Effects ◽  
Meta Analysis ◽  
People Living With Hiv ◽  
Funnel Plots ◽  
Sex With Men ◽  
Treat All ◽  
Living With Hiv

The incidence of herpes zoster (HZ) in patients infected with HIV is higher than that of the general population. However, the incidence of HZ in HIV patients receiving antiretroviral therapy (ART) remains unclear. This meta-analysis aimed to estimate the pooled incidence rate and risk factors for HZ in the post-ART era. We identified studies assessing the incidence of HZ in the post-ART era between 1 January 2000 and 28 February 2021, from four databases. Pooled risk ratios were calculated from 11 articles using a random-effects model. The heterogeneity of the included trials was evaluated by visually inspecting funnel plots, performing random-effects meta-regression and using I2 statistics. Of the 2111 studies screened, we identified 11 studies that were eligible for final inclusion in the systematic review and 8 studies that were eligible for a meta-analysis. The pooled incidence of HZ in the post-ART era (after the introduction of ART in 1997) was 2.30 (95% confidence interval (CI): 1.56–3.05) per 100 person years (PYs). The risks of incidence of HZ among people living with HIV included male sex (AOR: 4.35 (95% CI: 054–2.41)), men who have sex with men (AOR: 1.21 (95% CI: −0.76–1.13)), CD4 count < 200 cells/μL (AOR: 11.59 (95% CI: 0.53–4.38)) and not receiving ART (AOR: 2.89 (95% CI: −0.44–2.56)). The incidence of HZ is substantially lower among HIV infected patients receiving ART than those not receiving ART. Initiating ART immediately after diagnosis to treat all HIV-positive individuals is crucial to minimize the disease burden of HZ.

HIV detection from human serum with paper-based isotachophoretic RNA extraction and reverse transcription recombinase polymerase amplification

The Analyst ◽  
2021 ◽  
Author(s):  
Andrew T. Bender ◽  
Benjamin P. Sullivan ◽  
Jane Zhang ◽  
David C Juergens ◽  
Lorraine Lillis ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Human Serum ◽  
Reverse Transcription ◽  
Rna Extraction ◽  
Recombinase Polymerase Amplification ◽  
People Living With Hiv ◽  
Treatment Regimens ◽  
Living With Hiv

The number of people living with HIV continues to increase with the current total near 38 million, of which about 26 million are receiving antiretroviral therapy (ART). These treatment regimens...

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