Mechanisms of neuronal dysfunction in HIV-associated neurocognitive disorders

Abstract

HIV-associated neurocognitive disorder (HAND) is characterized by cognitive and behavioral deficits in people living with HIV. HAND is still common in patients that take antiretroviral therapies, although they tend to present with less severe symptoms. The continued prevalence of HAND in treated patients is a major therapeutic challenge, as even minor cognitive impairment decreases patient’s quality of life. Therefore, modern HAND research aims to broaden our understanding of the mechanisms that drive cognitive impairment in people with HIV and identify promising molecular pathways and targets that could be exploited therapeutically. Recent studies suggest that HAND in treated patients is at least partially induced by subtle synaptodendritic damage and disruption of neuronal networks in brain areas that mediate learning, memory, and executive functions. Although the causes of subtle neuronal dysfunction are varied, reversing synaptodendritic damage in animal models restores cognitive function and thus highlights a promising therapeutic approach. In this review, we examine evidence of synaptodendritic damage and disrupted neuronal connectivity in HAND from clinical neuroimaging and neuropathology studies and discuss studies in HAND models that define structural and functional impairment of neurotransmission. Then, we report molecular pathways, mechanisms, and comorbidities involved in this neuronal dysfunction, discuss new approaches to reverse neuronal damage, and highlight current gaps in knowledge. Continued research on the manifestation and mechanisms of synaptic injury and network dysfunction in HAND patients and experimental models will be critical if we are to develop safe and effective therapies that reverse subtle neuropathology and cognitive impairment.

Brain Volumetric Alterations in Preclinical HIV-Associated Neurocognitive Disorder Using Automatic Brain Quantification and Segmentation Tool

“…During the past decade, there has been an increasing interest in the mechanism, diagnosis, and treatment of HAND. However, the effective treatment of HAND has not been established, which indicates that the pathogenesis underlying the HAND remains controversial and unclear ( Irollo et al, 2021 ). In the absence of updated neuropathology research, much of the knowledge on HAND will have to rely on advanced neuroimaging technology, which can provide insights on macrolevel brain changes.…”

“…Further studies are necessary to validate whether the abnormalities described in our study are related to the pathogenesis of this condition. Previous research reported that reversing synaptic cartilage damage in animal models can restore cognitive function, so it highlights a promising treatment approach that has the potential to treat HAND ( Irollo et al, 2021 ). Moreover, the studies on the manifestations and mechanisms of synaptic damage and functional and structural network abnormity in preclinical HAND patients and experimental models may contribute to developing safe and effective therapeutic methods that reverse subtle neuropathological changes and cognitive impairment, while longitudinal research might assess the risk factors for developing HAND and the response to treatment.…”

Neurological complications during HIV infection

“…Continued research on the manifestation and mechanisms of neurological injury in HAND patients is needed. Animal models will be critical to help develop safe and effective therapies that reverse neuropathology and cognitive impairment [8].…”

“…Consequently, HIV infection can often be associated with neurological damage, including neurocognitive impairment and HIV-associated dementia (HAD) [6,7]. Typical symptoms include loss of concentration, attention, and memory, irritability, depression, and slowed movements [8]. The severity of the symptoms can range from asymptomatic to HAD in the most severe cases.…”

“…The severity of the symptoms can range from asymptomatic to HAD in the most severe cases. memory and executive functions [8]. Because HIV replication in the CNS occurs principally in microglia (the resident macrophage-type cells), is thought that both, direct effects of viral proteins, and indirect effects mediated by microglia activation and secretion of neurotoxic products can contribute to neuronal damage [9,10].…”