HIV-Associated Neurocognitive Impairment in the Modern ART Era: Are We Close to Discovering Reliable Biomarkers in the Setting of Virological Suppression?

Abstract

The prevalence of the most severe forms of HIV-associated neurocognitive disorders (HAND) is decreasing due to worldwide availability and high efficacy of antiretroviral treatment (ART). However, several grades of HIV-related cognitive impairment persist with effective ART and remain a clinical concern for people with HIV (PWH). The pathogenesis of these cognitive impairments has yet to be fully understood and probably multifactorial. In PWH with undetectable peripheral HIV-RNA, the presence of viral escapes in cerebrospinal fluid (CSF) might explain a proportion of cases, but not all. Many other mechanisms have been hypothesized to be involved in disease progression, in order to identify possible therapeutic targets. As potential indicators of disease staging and progression, numerous biomarkers have been used to characterize and implicate chronic inflammation in the pathogenesis of neuronal injuries, such as certain phenotypes of activated monocytes/macrophages, in the context of persistent immune activation. Despite none of them being disease-specific, the correlation of several CSF cellular biomarkers to HIV-induced neuronal damage has been investigated. Furthermore, recent studies have been evaluating specific microRNA (miRNA) profiles in the CSF of PWH with neurocognitive impairment (NCI). The aim of the present study is to review the body of evidence on different biomarkers use in research and clinical settings, focusing on PWH on ART with undetectable plasma HIV-RNA.

The Glutamate System as a Crucial Regulator of CNS Toxicity and Survival of HIV Reservoirs

“…If systemic HIV-1 replication is not controlled by ART, localized HIV-1-CNS replication and infection results in HIV-1 encephalitis and dementia (Gatanaga et al, 1999 ; Bingham et al, 2011 ; Gelman et al, 2013 ; Gelman, 2015 ; de Almeida et al, 2017 ; Mangus et al, 2018 ). However, in the current ART era, CNS damage is mild due to controlled peripheral and CNS replication as well as limited HIV-1 infection; despite this, 50% of the HIV-1-infected individuals still show significant signs of cognitive impairment, but the mechanism of CNS dysfunction is unknown (Eggers et al, 2017 ; Yoshimura, 2017 ; Bandera et al, 2019 ; Fernandes and Pulliam, 2019 ; Kim-Chang et al, 2019 ; Paul, 2019 ; Portilla et al, 2019 ; Swinton et al, 2019 ; Angelovich et al, 2020 ). Several groups have proposed that CNS damage in the current ART era corresponds to a combination of HIV-1 reservoirs within the brain, low level expression and secretion of viral proteins, as well as associated inflammation (Wong and Yukl, 2016 ; Veenstra et al, 2017 , 2019 ).…”

Nef-induced CCL2 Expression Contributes to HIV/SIV Brain Invasion and Neuronal Dysfunction

“…Moreover, it is difficult to accurately differentiate between age-related neurodegeneration, other neurodegenerative diseases and HIV-associated neurocognitive disorders (HAND) (12). However, attempts have been made to identify biomarkers to diagnose neurocognitive impairment in HIV-infected persons and activated monocytes/macrophages and C-C motif chemokine ligand 2 (CCL2) appear to be the most promising amongst them (13).…”

Astrocytes, HIV and the Glymphatic System: A Disease of Disrupted Waste Management?

“…With the development of cART, PWH typically have normal life spans (Bandera et al, 2019 ). While cART has dramatically increased the life expectancy of PWH, it has also brought attention to an array of neurocognitive issues, collectively known as HAND.…”

“…Limited information is available regarding the optimal clinical management of older PWH (Chen et al, 2019 ; Guaraldi et al, 2019 ; Guo and Buch, 2019 ). Chronic neuroinflammation has been associated with altered synaptic connectivity and BBB function, and with neuronal injury (Bandera et al, 2019 ; Guaraldi et al, 2019 ). In the CNS, age-associated neuroinflammation is also linked with impaired waste clearance (Cassol et al, 2014 ).…”