Monray Edward Williams

Despite effective combination antiretroviral therapy (cART), HIV-1 infection remains associated with chronic neurological complications and persistent central nervous system (CNS) dysfunction. HIV-associated brain injury (HABI) occurs primarily through indirect mechanisms mediated by viral proteins released from infected and reservoir cells within the CNS, rather than through direct neuronal infection. Over the past decade, NeuroHIV research has increasingly recognized Tat, gp120, Vpr, and Nef as persistent regulators of interconnected neuroimmune, neurovascular, metabolic, and synaptic pathways that collectively sustain CNS injury. Emerging evidence demonstrates that these viral proteins promote chronic microglial activation, mitochondrial dysfunction, inflammasome signalling, oxidative stress, ferroptosis, lysosomal dysfunction, extracellular-vesicle signalling, synaptic remodelling, and blood–brain barrier disruption through overlapping and convergent mechanisms that may persist independently of active viral replication. Recent advances in human-based models and systems-level approaches further support the concept that HABI reflects a chronic network of neuroimmune, neurovascular, and metabolic dysfunction rather than isolated neuronal toxicity. This review synthesizes recent mechanistic advances in HIV-1 viral protein-mediated neuropathogenesis, highlights emerging pathways with translational potential, and discusses future directions for developing targeted therapeutic strategies to preserve long-term neurological health in people living with HIV.

HIV remains a significant public health issue, with 1.3 million new infections and 630,000 deaths annually, and 40.8 million people living with HIV (PLHIV) globally in 2024. Although antiretroviral therapy (ART) suppresses viral replication, it does not eradicate the virus, and metabolic dysregulation persists despite treatment. Metabolomics allows for a detailed investigation of these alterations; however, targeted metabolomics studies in ART‐treated PLHIV are limited, and there is no consensus on consistently dysregulated metabolites in PLHIV compared to healthy controls (HCs). This systematic review aimed to identify frequently investigated metabolites and key metabolic alterations in ART‐treated PLHIV. A search strategy was designed for this study. PubMed, Scopus, and Web of Science were searched to identify relevant articles. We collected all search results in a reference manager and assessed titles and abstracts, as well as the full‐text of the articles, for inclusion eligibility according to PRISMA guidelines. A total of 3217 studies were identified, of which 15 studies met the inclusion criteria. The review included 15 studies, comprising 886 PLHIV and 389 HCs. The most investigated metabolites were glutamine, tryptophan (Trp), kynurenine (Kyn), Kyn/Trp ratio, glycine, and ornithine. Consistent trends showed lower glutamine and glycine, and higher Kyn/Trp and ornithine, in PLHIV compared to HCs. Notably, metabolic dysregulation persisted in PLHIV despite viral suppression. Furthermore, studies conducted in the Global North more frequently reported metabolic dysregulation in PLHIV relative to HCs, compared with studies from the Global South, potentially reflecting regional variation or methodological differences. These findings offer insight into the targeted metabolic profiles of ART‐treated PLHIV using metabolomics and suggest that metabolites such as glutamine, glycine, Kyn/Trp ratio and ornithine may play important roles in understanding HIV‐1 pathogenesis in the modern ART‐era.

HIV-1 remains a major global health concern, exerting detrimental effects not only on the immune system but also on the central nervous system (CNS). Soon after HIV-1 infection, the virus can breach the blood–brain barrier (BBB), initiating processes that result in neuronal damage and cell death. These effects manifest clinically as a spectrum of cognitive, behavioural, and motor impairments collectively termed HIV-associated neurocognitive disorders (HAND). Among the viral proteins implicated in CNS pathology, the Trans-Activator of Transcription (Tat) protein stands out due to its pronounced neurotoxic and neurotropic characteristics. Tat is secreted by infected cells and can accumulate in the CNS, persisting even in individuals undergoing effective antiretroviral therapy (ART), thereby contributing to ongoing neurocognitive complications. Although Tat has been extensively studied since the 1980s, current literature examining its effects within the context of modern treatment regimens remains sparse. This chapter offers a comprehensive and updated review of the role of HIV-1 Tat in neuropathogenesis, drawing on research from the past 25 years to highlight its contribution to HAND and to outline potential avenues for therapeutic advancement.

HIV remains a global health challenge, affecting millions of individuals worldwide. While combination antiretroviral therapy (cART) significantly reduces viral loads to undetectable levels, it does not eradicate the virus completely, and a compromised host immune system persists. Traditionally, HIV-1 research has largely focused on elucidating the mechanisms of viral replication, characterising host immune responses, specifically inflammation, and developing effective antiretroviral therapies. However, comparatively less emphasis has historically been placed on understanding the metabolic alterations associated with HIV-1 infection. Metabolomics, a powerful tool that provides a functional understanding of the systemic metabolic changes induced by HIV and cART, is increasingly recognised for its potential to reveal the complex interplay between chronic inflammation, metabolic reprogramming, and long-term health outcomes. This chapter explores the critical metabolic pathways disrupted by HIV infection in the modern cART era, focusing on amino acid, glucose, microbiome, and lipid metabolism. Using metabolomic profiling, this chapter highlights persistent immunometabolic dysfunctions in people living with HIV, highlighting pathways of comorbidity risk and offering insights into therapeutic interventions to improve patient outcomes in the modern cART era.

HIV enters the central nervous system (CNS) early, disrupting neurometabolism and inducing chronic neuroinflammation that results in the development of neurocognitive symptoms and neurodevelopmental delay in children infected with HIV. In children, neurocognitive presentation is often more severe than in adults, due to early and prolonged exposure to the virus. Tuberculous meningitis (TBM), another major pediatric CNS infection and often an opportunistic co-infection in HIV, carries high morbidity and mortality but remains difficult to diagnose with existing tests. Metabolomics provides a promising complementary diagnostic approach. We used ¹H-NMR and GCxGC-TOF/MS to compare cerebrospinal fluid (CSF) metabolic profiles from children with HIV, TBM, HIV-TBM co-infection, viral meningitis, and controls that were uninfected but presented with neurological symptoms (e.g., seizures, raised intracranial pressure, brainstem dysfunction, infarction, etc.). Profiles were analyzed using univariate (ANOVA, Wilcoxon with FDR correction) and multivariate (PCA) methods. The discriminatory performance of candidate metabolites and biomarker panels was evaluated using receiver operating characteristic (ROC) analysis, which included the area under the curve (AUC), sensitivity, specificity, likelihood ratios, diagnostic odds ratios, and Youden's index to determine the optimal cut-offs. PCA demonstrated clear separation of viral and bacterial CNS infections. HIV was characterized by sugar alcohols, ketone bodies, and guanidinoacetate, whereas TBM showed a strong glycolytic and amino acid catabolic signature dominated by lactate, alanine, creatine, and fatty acid derivatives. Distinct CSF biosignatures can differentiate HIV and TBM in children, supporting their potential for future diagnostic applications and for advancing understanding of CNS pathogenesis in these infections.

Background: Depression is common in people living with HIV and may involve immune–metabolic dysregulation. Altered tryptophan (Trp) metabolism via the kynurenine (Kyn) pathway, particularly quinolinic acid (QUIN), has been linked to neuroinflammation and depression, yet data from South Africans with HIV-1 subtype C are limited. Methods: In this exploratory cohort, treatment-naïve adults with HIV were assessed at baseline in 2010 (n = 69) and followed up in 2015 (n = 40). Targeted LC-MS/MS quantified Trp–Kyn metabolites (Trp, Kyn, KA, QUIN) and ELISAs measured immune markers (suPAR, IL-6, hsCRP, sCD163, NGAL). Depressive symptoms were evaluated using the PHQ-9 at baseline and follow-up. Results: Baseline QUIN was associated with the PHQ-9 total score (adjusted R²=0.245; β=0.417; p = 0.004, p(Hochberg) = 0.044) and also increased odds of depression risk (OR=61.1; 95%CI 2.24–1664.76; p = 0.015, p(Hochberg) = 0.030) at baseline. Baseline NGAL was significantly lower in the follow-up group with self-harm thoughts compared to the group with no–self-harm thoughts (p = 0.008) and lower NGAL predicted greater odds of follow-up self-harm thoughts (OR = 0.007, 95% CI: <0.001–0.572, p = 0.027, p(Hochberg) = 0.027). When PHQ-9 subscales were examined, baseline QUIN, Kyn, hsCRP, and suPAR showed positive associations with the baseline somatic subscale (β range= 0.34–0.57, all p < 0.01), whereas the baseline cognitive–affective subscale was not associated with any marker. No baseline markers were associated with follow-up depression risk or scores. Over five years, suPAR decreased whereas hsCRP did not change significantly, however changes in these markers over time did not reveal any associations with the PHQ-9 total or subscale scores. Conclusions: In this exploratory cohort, higher peripheral QUIN may be linked to depression risk, particularly with somatic rather than cognitive–affective symptom dimensions. Lower baseline NGAL was the only marker associated with later self-harm thoughts, suggesting a potential neuroimmune signal that warrants further investigation. Larger, adequately powered longitudinal studies with repeated metabolomic assessments are warranted to confirm this finding and clarify temporal and causal relationships between immune–metabolic dysregulation and specific depressive symptom profiles.