¶ HIV-Associated Neurocognitive Disorders (HAND)
Hiv Associated Neurocognitive Disorders (Hand) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
HIV-Associated Neurocognitive Disorders (HAND) encompass a spectrum of neurocognitive impairments caused by human immunodeficiency virus (HIV) infection of the central nervous system (CNS). Despite the success of combination antiretroviral therapy (cART) in suppressing systemic viral loads and extending life expectancy, HAND remains a major complication affecting an estimated 30–60% of people living with HIV (PLWH) worldwide 1(https://pmc.ncbi.nlm.nih.gov/articles/PMC4937456/). The brain serves as a viral sanctuary where HIV can persist and replicate even when peripheral viral suppression is achieved, leading to chronic [neuroinflammation[/mechanisms/[neuroinflammation[/mechanisms/[neuroinflammation[/mechanisms/[neuroinflammation--TEMP--/mechanisms)--FIX--, synaptic injury, and progressive neurocognitive decline 2(https://pmc.ncbi.nlm.nih.gov/articles/PMC10615506/).
HAND was first recognized in the 1980s as AIDS dementia complex (ADC), a devastating condition causing severe cognitive, motor, and behavioral dysfunction. With the advent of cART in the mid-1990s, the incidence of the most severe form (HIV-associated dementia) has declined dramatically, but milder forms of neurocognitive impairment have become more prevalent, representing an emerging challenge in chronic HIV management 3(https://emedicine.medscape.com/article/1166894-overview).
The 2007 Frascati criteria established a standardized classification system for HAND, defining three categories of increasing severity 4(https://www.researchgate.net/figure/Frascati-criteria-for-HAND-diagnosis-22_tbl1_379853773):
- Performance ≥1 standard deviation (SD) below the normative mean in ≥2 cognitive domains on standardized neuropsychological testing
- No interference with everyday functioning
- Prevalence: approximately 26% of PLWH 5(https://pmc.ncbi.nlm.nih.gov/articles/PMC8235728/)
- Represents the most common HAND subtype in the cART era
- Performance ≥1 SD below normative data in ≥2 cognitive domains
- Mild-to-moderate interference with daily functioning (work, home management, social activities)
- Prevalence: approximately 8.5% of PLWH 5(https://pmc.ncbi.nlm.nih.gov/articles/PMC8235728/)
- Performance ≥2 SD below normative data in ≥2 cognitive domains
- Marked interference with daily functioning
- Prevalence: approximately 2.1% of PLWH in the cART era (down from 15–20% pre-cART) 5(https://pmc.ncbi.nlm.nih.gov/articles/PMC8235728/)
- Historically the most feared neurological complication of AIDS
Overall estimated prevalence of any HAND category is approximately 44.9%, making it one of the most common neurological complications of HIV infection 5(https://pmc.ncbi.nlm.nih.gov/articles/PMC8235728/).
¶ CNS Entry and Viral Reservoirs
HIV enters the CNS early during primary infection via a "Trojan horse" mechanism, crossing the [blood-brain barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- within infected monocytes and CD4+ T lymphocytes [[1]))]https://pmc.ncbi.nlm.nih.gov/articles/PMC4937456/). Once inside the CNS, the virus productively infects [microglia[/doi:10.1093/brain/awaa219">2[/doi:10.1093/brain/awaa219">2[/doi:10.1093/brain/awaa219">2--TEMP--/doi:10.1093/brain/awaa219">2<)--FIX--(https://pmc.ncbi.nlm.nih.gov/articles/PMC10615506/).
HIV enters the CNS early during primary infection via a "Trojan horse" mechanism, crossing the [blood-brain barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- within infected monocytes and CD4+ T lymphocytes 1(https://pmc.ncbi.nlm.nih.gov/articles/PMC4937456/). Once inside the CNS, the virus productively infects microglia/.
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HIV-1 Tat (transactivator of transcription): Secreted by infected cells, Tat directly impairs [synaptic] function, disrupts [calcium] homeostasis, promotes [neuronal apoptosis], and potentiates [excitotoxicity[/entities/[excitotoxicity[/entities/[excitotoxicity[/entities/[excitotoxicity--TEMP--/entities)--FIX-- through [NMDA receptor[/entities/[nmda-receptor[/entities/[nmda-receptor[/entities/[nmda-receptor--TEMP--/entities)--FIX-- receptor]] receptor dysregulation [[1]))]https://pmc.ncbi.nlm.nih.gov/articles/PMC4937456/)
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gp120 (envelope glycoprotein): Triggers [oxidative stress[/mechanisms/[oxidative-stress[/mechanisms/[oxidative-stress[/mechanisms/[oxidative-stress--TEMP--/mechanisms)--FIX-- and [mitochondrial dysfunction[/mechanisms/[mitochondrial-dysfunction[/mechanisms/[mitochondrial-dysfunction[/mechanisms/[mitochondrial-dysfunction--TEMP--/mechanisms)--FIX-- in [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX--, and activates [microglia[/cell-types/[microglia[/cell-types/[microglia[/cell-types/[microglia--TEMP--/cell-types)--FIX--:69-81. [doi:10.1038/nri1527" title="^6]: Gonzalez-Scarano F, Martin-Garcia J. The neuropathogenesis of AIDS. Nat Rev Immunol. 2005;5(1):69-81. doi:10.1038/nri1527">6))
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Vpr (viral protein R): Induces cell cycle arrest and [apoptosis[/entities/[apoptosis[/entities/[apoptosis[/entities/[apoptosis--TEMP--/entities)--FIX-- in [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- and glia [[1]))]https://pmc.ncbi.nlm.nih.gov/articles/PMC4937456/)
Several HIV-encoded proteins exert direct neurotoxic effects:
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HIV-1 Tat (transactivator of transcription): Secreted by infected cells, Tat directly impairs [synaptic] function, disrupts [calcium] homeostasis, promotes [neuronal apoptosis], and potentiates [excitotoxicity[/entities/[excitotoxicity[/entities/[excitotoxicity[/entities/[excitotoxicity--TEMP--/entities)--FIX-- through [NMDA receptor[/entities/[nmda-receptor[/entities/[nmda-receptor[/entities/[nmda-receptor--TEMP--/entities)--FIX-- receptor] receptor] receptor dysregulation 1(https://pmc.ncbi.nlm.nih.gov/articles/PMC4937456/)
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gp120 (envelope glycoprotein): Triggers [oxidative stress[/mechanisms/[oxidative-stress[/mechanisms/[oxidative-stress[/mechanisms/[oxidative-stress--TEMP--/mechanisms)--FIX-- and [mitochondrial dysfunction[/mechanisms/[mitochondrial-dysfunction[/mechanisms/[mitochondrial-dysfunction[/mechanisms/[mitochondrial-dysfunction--TEMP--/mechanisms)--FIX-- in [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX--, and activates microglia/
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Vpr (viral protein R): Induces cell cycle arrest and [apoptosis[/entities/[apoptosis[/entities/[apoptosis[/entities/[apoptosis--TEMP--/entities)--FIX-- in [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- and glia 1(https://pmc.ncbi.nlm.nih.gov/articles/PMC4937456/)
- Pro-inflammatory cytokines: TNF-α, IL-1β, IL-6, and interferon-γ
- Chemokines: CCL2/MCP-1, CXCL10, and fractalkine
- [reactive oxygen species[/mechanisms/[oxidative-stress[/mechanisms/[oxidative-stress[/mechanisms/[oxidative-stress--TEMP--/mechanisms)--FIX-- and nitrogen species
- Quinolinic acid (an [NMDA receptor[/entities/[nmda-receptor[/entities/[nmda-receptor[/entities/[nmda-receptor--TEMP--/entities)--FIX-- receptor] receptor] agonist and excitotoxin)
- Platelet-activating factor and arachidonic acid metabolites
Chronic [neuroinflammation[/mechanisms/[neuroinflammation[/mechanisms/[neuroinflammation[/mechanisms/[neuroinflammation--TEMP--/mechanisms)--FIX-- is a central driver of HAND pathogenesis. HIV-infected microglia.
Dysregulation of [glutamate[/entities/[glutamate[/entities/[glutamate[/entities/[glutamate--TEMP--/entities)--FIX-- neurotransmission is a key mechanism in HAND. Infected macrophages and activated microglia/.
HIV infection leads to increased permeability of the [blood-brain barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- through multiple mechanisms: viral proteins (Tat and gp120) directly disrupt tight junction proteins, inflammatory mediators degrade the basement membrane, and activated monocytes transmigrate across the endothelium. [BBB[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- breakdown allows entry of viral particles, infected cells, and neurotoxic plasma proteins into the brain parenchyma 2(https://pmc.ncbi.nlm.nih.gov/articles/PMC10615506/).
HAND involves vulnerability of neural circuits caused by [synaptic] degeneration and abnormal [dendritic] pruning. Loss of synaptic density, particularly in the [hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus--TEMP--/brain-regions)--FIX-- and [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX--, correlates more closely with cognitive impairment than neuronal loss, paralleling mechanisms observed in [Alzheimer's disease[/diseases/[alzheimers[/diseases/[alzheimers[/diseases/[alzheimers--TEMP--/diseases)--FIX-- 7(https://www.mdpi.com/1422-0067/25/20/11170).
¶ Cognitive Domains Affected
HAND typically affects the following cognitive domains:
- Attention and working memory: Difficulty concentrating and processing information
- Executive function: Impaired planning, decision-making, and mental flexibility
- Processing speed: Slowed information processing
- Learning and memory: Difficulty encoding new information (retrieval typically better preserved than in [Alzheimer's Disease)
- Motor function: Psychomotor slowing, fine motor impairment, gait abnormalities
- Language: Generally preserved until advanced stages
¶ Behavioral and Psychiatric Symptoms
- Apathy and motivational deficits
- Depression (highly prevalent, complicating diagnosis)
- Irritability and emotional lability
- Social withdrawal
- In HAD: personality changes, psychosis, and mania may occur
- International HIV Dementia Scale (IHDS): A brief bedside screening tool assessing timed finger tapping, timed alternating hand sequences, and recall. Pooled sensitivity for HAND detection is approximately 62%, with higher sensitivity for HAD (74.3%) [[5]))]https://pmc.ncbi.nlm.nih.gov/articles/PMC8235728/)
- HIV Dementia Scale (HDS): Original screening tool with higher sensitivity for HAD than milder forms
- Montreal Cognitive Assessment (MoCA): Commonly used but not HIV-specific
- International HIV Dementia Scale (IHDS): A brief bedside screening tool assessing timed finger tapping, timed alternating hand sequences, and recall. Pooled sensitivity for HAND detection is approximately 62%, with higher sensitivity for HAD (74.3%) 5(https://pmc.ncbi.nlm.nih.gov/articles/PMC8235728/)
- HIV Dementia Scale (HDS): Original screening tool with higher sensitivity for HAD than milder forms
- Montreal Cognitive Assessment (MoCA): Commonly used but not HIV-specific
Formal neuropsychological testing across multiple cognitive domains remains the gold standard for HAND diagnosis. A comprehensive battery should assess at least five cognitive areas, with demographically adjusted norms accounting for age, education, and cultural background 3(https://emedicine.medscape.com/article/1166894-overview).
- MRI: Cortical and subcortical atrophy, white matter hyperintensities, [basal ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia--TEMP--/brain-regions)--FIX-- volume loss
- Diffusion tensor imaging (DTI): White matter microstructural changes preceding macroscopic damage
- Functional MRI: Altered network connectivity, particularly in frontostriatal circuits
- MR spectroscopy: Elevated choline and myoinositol (glial activation markers), decreased N-acetylaspartate (neuronal integrity marker) 8(https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2025.1467175/full)
- CSF markers: [Neurofilament light chain[/proteins/[nfl-protein[/proteins/[nfl-protein[/proteins/[nfl-protein--TEMP--/proteins)--FIX-- ([NfL[/entities/[neurofilament-light[/entities/[neurofilament-light[/entities/[neurofilament-light--TEMP--/entities)--FIX--, CSF HIV RNA, [GFAP[/entities/[glial-fibrillary-acidic-protein[/entities/[glial-fibrillary-acidic-protein[/entities/[glial-fibrillary-acidic-protein--TEMP--/entities)--FIX--, and inflammatory cytokines
- Plasma markers: [NfL[/entities/[neurofilament-light[/entities/[neurofilament-light[/entities/[neurofilament-light--TEMP--/entities)--FIX-- may serve as a non-invasive biomarker of CNS injury 3(https://emedicine.medscape.com/article/1166894-overview)
cART remains the cornerstone of HAND management. Selection of ART regimens with high CNS penetration-effectiveness (CPE) scores may improve neurological outcomes, though this remains debated 6(https://link.springer.com/article/10.1186/s12987-020-00204-5). Key considerations include:
- Early ART initiation to limit viral seeding of the CNS
- Optimization of regimens for [BBB[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- penetration
- Management of persistent CSF viral escape
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[Memantine[/treatments/[memantine[/treatments/[memantine[/treatments/[memantine--TEMP--/treatments)--FIX--: [NMDA receptor[/entities/[nmda-receptor[/entities/[nmda-receptor[/entities/[nmda-receptor--TEMP--/entities)--FIX-- receptor]] receptor antagonist to mitigate excitotoxicity
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Minocycline: Anti-inflammatory and neuroprotective properties
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Lithium: [GSK-3β[/entities/[gsk3-beta[/entities/[gsk3-beta[/entities/[gsk3-beta--TEMP--/entities)--FIX-- inhibition and neuroprotection
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Statins: Anti-inflammatory effects and [BBB[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- stabilization
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Intranasal insulin: Targeting [insulin signaling] pathways in the brain
No FDA-approved medications specifically target HAND. Investigational approaches include 6(https://link.springer.com/article/10.1186/s12987-020-00204-5):
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[Memantine[/treatments/[memantine[/treatments/[memantine[/treatments/[memantine--TEMP--/treatments)--FIX--: [NMDA receptor[/entities/[nmda-receptor[/entities/[nmda-receptor[/entities/[nmda-receptor--TEMP--/entities)--FIX-- receptor] receptor] receptor antagonist to mitigate excitotoxicity
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Minocycline: Anti-inflammatory and neuroprotective properties
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Lithium: [GSK-3β[/entities/[gsk3-beta[/entities/[gsk3-beta[/entities/[gsk3-beta--TEMP--/entities)--FIX-- inhibition and neuroprotection
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Statins: Anti-inflammatory effects and [BBB[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier[/entities/[blood-brain-barrier--TEMP--/entities)--FIX-- stabilization
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Intranasal insulin: Targeting [insulin signaling] pathways in the brain
- Cognitive rehabilitation: Structured training programs targeting impaired domains
- Physical exercise: Regular aerobic exercise associated with improved cognitive outcomes
- Psychosocial support: Addressing depression, substance use, and social isolation
- Management of comorbidities: Cardiovascular disease, metabolic syndrome, hepatitis C co-infection 9(https://www.sciencedirect.com/science/article/abs/pii/S0022510X25000279)
HAND shares several pathogenic mechanisms with classic neurodegenerative diseases, particularly [Alzheimer's disease[/diseases/[alzheimers[/diseases/[alzheimers[/diseases/[alzheimers--TEMP--/diseases)--FIX--:
- [Amyloid] pathology: PLWH show accelerated [amyloid-beta[/entities/[amyloid-beta[/entities/[amyloid-beta[/entities/[amyloid-beta--TEMP--/entities)--FIX-- deposition, and HIV-1 Tat inhibits [neprilysin[/proteins/[neprilysin[/proteins/[neprilysin[/proteins/[neprilysin--TEMP--/proteins)--FIX--, a major [Aβ[/entities/[amyloid-beta[/entities/[amyloid-beta[/entities/[amyloid-beta--TEMP--/entities)--FIX---degrading enzyme 7(https://www.mdpi.com/1422-0067/25/20/11170)
- [Tau[/entities/[tau-protein[/entities/[tau-protein[/entities/[tau-protein--TEMP--/entities)--FIX-- pathology]: Hyperphosphorylated tau] is found in HIV-positive brains, particularly in those with cognitive impairment
- [neuroinflammation[/mechanisms/[neuroinflammation[/mechanisms/[neuroinflammation[/mechanisms/[neuroinflammation--TEMP--/mechanisms)--FIX--: Chronic microglial activation is a shared feature
- [oxidative stress[/mechanisms/[oxidative-stress[/mechanisms/[oxidative-stress[/mechanisms/[oxidative-stress--TEMP--/mechanisms)--FIX--: Mitochondrial dysfunction and [ROS[/mechanisms/[oxidative-stress[/mechanisms/[oxidative-stress[/mechanisms/[oxidative-stress--TEMP--/mechanisms)--FIX-- accumulation are central to both HAND and AD
- [autophagy[/entities/[autophagy[/entities/[autophagy[/entities/[autophagy--TEMP--/entities)--FIX---lysosomal dysfunction]: HIV proteins impair [autophagy[/entities/[autophagy[/entities/[autophagy[/entities/[autophagy--TEMP--/entities)--FIX--, leading to accumulation of toxic protein aggregates
- Accelerated aging: PLWH show features of premature brain aging, including early-onset cognitive decline and reduced brain volume
These overlapping mechanisms have led to the hypothesis that HIV infection may accelerate or predispose to [Alzheimer]'s-type neurodegeneration 7(https://www.mdpi.com/1422-0067/25/20/11170).
The study of Hiv Associated Neurocognitive Disorders (Hand) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- [microglia[/[Memantine[/[Memantine[/[Memantine[/[Memantine[/[Memantine[/Memantine(/treatments/memantine)
- ^1]: Saylor D, et al. HIV-associated neurocognitive disorder - pathogenesis and therapeutic prospects. J Neurovirol. 2019;25(5):656-666. DOI:10.1007/s13365-019-00764-1
- ^2]: Heaton RK, et al. HIV-associated neurocognitive disorders in the modern era: prevalence, risk factors, and biomarkers. Brain. 2020;143(10):3126-3143. DOI:10.1093/brain/awaa219
- ^3]: Clifford DB, Ances BM. HIV-associated neurocognitive disorder (HAND). Lancet Infect Dis. 2013;13(11):976-986. DOI:10.1016/S1473-3099(1370269-X
- ^4]: Gelman BB, et al. Neuropathology of HAND. J Neurovirol. 2019;25(5):667-684. DOI:10.1007/s13365-019-00757-8
- ^5]: Kaul M, et al. HIV-1 associated dementia: a role for [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX--. Clin Neurosci Res. 2005;5(5):315-328. DOI:10.1016/j.cnr.2005.08.017
- ^6]: Gonzalez-Scarano F, Martin-Garcia J. The neuropathogenesis of AIDS. Nat Rev Immunol. 2005;5(1):69-81. DOI:10.1038/nri1527
- ^7]: Ellis R, et al. HIV-associated neurocognitive disorders in the era of combined antiretroviral therapy. Lancet Infect Dis. 2020;20(7):e162-e171. DOI:10.1016/S1473-3099(2030143-4
- ^8]: Sacktor N, et al. HIV-associated cognitive impairment in the era of combined antiretroviral therapy. Neurology. 2016;86(16):1537-1544. DOI:10.1212/WNL.0000000000002590
- ^9]: Valcour V, et al. HIV infection and dementia in older adults. Clin Infect Dis. 2006;42(10):1449-1454. DOI:10.1086/503424
- ^10]: Masliah E, et al. Neurodegeneration and synaptic impairment in AIDS. J Neurovirol. 2002;8(6):542-547. DOI:10.1080/13550280290100491
- [Saylor D, Dickens AM, Sacktor N, et al. (2016]. HIV-associated neurocognitive disorder — pathogenesis and prospects for treatment. Nature Reviews Neurology, 12(4), 234-248. PMC)
- [Obeagu EI, Obeagu GU. (2023]. HIV-related neurocognitive disorders: Diagnosis, treatment, and mental health implications: A review. Medicine, 102(40), e35652. PMC)
- [Moulignier A. (2024]. HIV-Associated Neurocognitive Disorder (HAND). Medscape. Medscape)
- [Antinori A, Arendt G, Becker JT, et al. (2007]. Updated research nosology for HIV-associated neurocognitive disorders. Neurology, 69(18), 1789-1799. ResearchGate)
- [Patel S, Engelbrecht E,"; et al. (2021]. International HIV Dementia Scale for HIV-associated neurocognitive disorders: a systematic review and meta-analysis. Diagnostics, 11(6), 1124. PMC)
- [Eggers C, Arendt G, Hahn K, et al. (2017]. Potential pharmacological approaches for the treatment of HIV-1 associated neurocognitive disorders. Fluids and Barriers of the CNS, 14(1), 1-12. Springer)
- [Canet G, Sinyuk M, Bhatt N, et al. (2024]. HIV-Associated Neurocognitive Disorder (HAND) and [Alzheimer]'s Disease Pathogenesis: Future Directions for Diagnosis and Treatment. International Journal of Molecular Sciences, 25(20), 11170. MDPI)
- [Chen Y, Liu J, Zhou L, et al. (2025]. Decoding HIV-associated neurocognitive disorders: a new perspective from multimodal connectomics. Frontiers in Neurology, 16, 1467175. Frontiers)
- [Singh M, Kaur J, Verma A. (2025]. HIV-associated neurocognitive disorders (HAND): Optimal diagnosis, antiviral therapy, pharmacological treatment, management, and future scopes. Journal of the Neurological Sciences, 468, 123279. ScienceDirect)
- [Guo Y, Li X, et al. (2025]. Development of research on HIV-associated neurocognitive disorder and emerging trends. Frontiers in Immunology, 16, 1478187. Frontiers)