Host single nucleotide polymorphisms and biomarkers of neuronal damage and inflammation in people living with HIV.

OBJECTIVES: Blood-brain barrier impairment is frequent in people living with human immunodeficiency virus (PLWHIV), affecting the penetration of target cells and antiretrovirals into the central nervous system, through transporters (e.g. ABCB1), leading to neuroinflammation. This study aimed to identify variants of genes encoding transporters able to predict neuroinflammation biomarker levels. METHODS: Cerebrospinal fluid (CSF) and plasma samples were obtained from PLWHIV. The CSF biomarkers were quantified by commercial assays. Genetic variants were evaluated through real-time polymerase chain reaction (PCR). RESULTS: A total of 107 PLWHIV (163 samples) were included in the study: 79% were male, median age was 48.5 years, CD4% was 25%, and HIV-associated neurocognitive disorder (HAND) was observed in 17.8%. The ABCB1 2677G>T genetic variant showed a different allelic distribution according to the clinical group (P = 0.026). In linear regression analyses, HIV-related central nervous system disorders, ABCG2 1194+928CC genotype, log viral load, CSF-to-serum albumin ratio, ß-1,42 levels, and CSF proteins were retained in the final model as factors independently associated with CSF neopterin levels; CSF proteins and integrase inhibitor use were associated with CSF tau level in the multivariate model. Phospho-tau regression analysis reported the ABCB1 2677GT/TT genotype and CSF proteins as predictors in the final model; sex, protease inhibitors, neopterin, and ABCB1 2677 GT/ TT genotype were predictors in the multivariate regression for ß-1,42. CONCLUSIONS: For the first time, pharmacogenetic and clinical features were found to be predictors of neuro-inflammation biomarkers.

[Rapidly progressive dementia as the initial presentation of human immunodeficiency virus infection].

Dementia associated with human immunodeficiency virus (HIV) is currently a rare cause of rapidly progressive dementia. Its appearance is not only limited to the late phases of the disease, but can sometimes be the presenting symptom. We present the case of a patient who debuted with anxious-depressive symptoms and rapid cognitive deteri-oration with early repercussions on his daily functionality. HIV was detected in the study, with a higher viral load in cerebrospinal fluid than in plasma. Despite a torpid course at the beginning, antiretroviral therapy brought about a progressive improvement in the cognitive sphere, consistent with the decrease in the viral load. Although rare, HIV continues to be a cause of dementia that primary care and hospital care professionals should not forget. The relevance of its early diagnosis lies in its potentially reversible nature.

Demencia rápidamente progresiva como forma de presentación de infección por el virus de la inmunodeficiencia humana / Rapidly progressive dementia as the initial presentation of human immunodeficiency virus infection

La demencia asociada a virus de la inmunodeficiencia humana (VIH) es una causa de demencia rápidamente progresiva poco frecuente en la actualidad. Su aparición no se limita a las fases tardías de la enfermedad, sino que en ocasiones puede ser el síntoma de presentación. Presentamos el caso de un paciente que debutó con síntomas ansioso-depresivos y un rápido deterioro cognitivo con repercusión precoz en su funcionalidad diaria. En el estudio se detectó VIH con mayor carga viral en líquido cefalorraquídeo que en plasma. La terapia antirretroviral logró, a pesar de la tórpida evolución inicial, una mejora progresiva en la esfera cognitiva, congruente con la disminución de la carga viral. Aunque poco frecuente, el VIH sigue siendo una causa de demencia que los profesionales de atención primaria y hospitalaria no debemos olvidar. La importancia de su diagnóstico precoz radica en su carácter potencialmente reversible.(AU)

Dementia associated with human immunodeficiency virus (HIV) is currently a rare cause of rapidly progressive dementia. Its appearance is not only limited to the late phases of the disease, but can sometimes be the presenting symptom. We present the case of a patient who debuted with anxious-depressive symptoms and rapid cognitive deterioration with early repercussions on his daily functionality. HIV was detected in the study, with a higher viral load in cerebrospinal fluid than in plasma. Despite a torpid course at the beginning, antiretroviral therapy brought about a progressive improvement in the cognitive sphere, consistent with the decrease in the viral load. Although rare, HIV continues to be a cause of dementia that primary care and hospital care professionals should not forget. The relevance of its early diagnosis lies in its potentially reversible nature.(AU)

Higher Cerebrospinal Fluid Soluble Urokinase-type Plasminogen Activator Receptor, But Not Interferon γ-inducible Protein 10, Correlate With Higher Working Memory Deficits.

BACKGROUND: We hypothesized that the induction of monocyte activation biomarkers, especially soluble urokinase-type plasminogen activator receptor (suPAR) and interferon γ-inducible protein 10 (IP-10), is lower in HIV-1C than HIV-1B, owing to a defective Tat cysteine dimotif (C30S). METHODS: A total of 68 paired cerebrospinal fluid (CSF) and blood samples from people with HIV (PWH), free of CNS opportunistic infections, from a Southern Brazil outpatient HIV clinic were evaluated such as HIV-1B subtype (n = 27), HIV-1C (n = 26), other (n = 15), and 19 HIV-negative controls. The levels of suPAR, IP-10, neopterin, and ß2 microglobulin (ß2m) in the CSF and serum were quantified using different immunoassays. RESULTS: Overall, in PWH, increases in CSF suPAR, CSF/serum suPAR, and CSF/serum ß2m correlated with worse working memory deficits (r = 0.303, 0.353, and 0.289, respectively, all P < 0.05). The medians of IP-10, suPAR, neopterin, and ß2m in CSF and serum and the CSF/serum ratio and suPAR index were comparable between the HIV-1B and HIV-1C subtypes. CSF IP-10 and neopterin and serum IP-10 and suPAR levels were higher in PWH than the HIV-negative controls (P = 0.015, P = 0.001, P < 0.0001, and P < 0.001, respectively). The serum ß2m level was higher in HIV-associated dementia than neuropsychologically normal or asymptomatic (P = 0.024). DISCUSSION: We observed that higher levels of CSF suPAR and the suPAR quotient correlated with worse working memory deficit. Elevated levels of monocyte activation were similar in both HIV-1 B and C subtypes, providing no evidence of reduced neuropathogenicity of HIV-1 subtype C Tat compared with subtype B.

Cerebrospinal fluid immune markers and HIV-associated neurocognitive impairments: A systematic review.

HIV-1 is responsible for the development of a spectrum of cognitive impairments known as HIV-associated neurocognitive disorder (HAND). In the era of antiretroviral therapy (ART), HAND remains prevalent in people living with HIV (PLWH), despite low or undetectable viral loads. Persistent neuroinflammation likely plays an important role in the contributing biological mechanisms. Multiple cerebrospinal fluid (CSF) immune markers have been studied but it is unclear which markers most consistently correlate with neurocognitive impairment. We therefore conducted a systematic review of studies of the association of CSF immune markers with neurocognitive performance in ART-experienced PLWH. We aimed to synthesize the published data to determine consistent findings and to indicate the most noteworthy CSF markers of HAND. Twenty-nine studies were included, with 20 cross-sectional studies and 9 longitudinal studies. From the group of markers most often assayed, specific monocyte activation (higher levels of Neopterin, sCD163, sCD14) and neuroinflammatory markers (higher levels of IFN-γ, IL-1α, IL-7, IL-8, sTNFR-II and lower levels of IL-6) showed a consistent direction in association with HIV-associated neurocognitive impairment. Furthermore, significant differences exist in CSF immune markers between HIV-positive people with and without neurocognitive impairment, regardless of viral load and nadir/current CD4+ count. These markers may be useful in furthering our understanding of the neuropathology, diagnosis and prognosis of HAND. Studies using prospective designs (i.e. pre- and post-interventions), "multi-modal" methods (e.g. imaging, inflammation and neurocognitive evaluations) and utilizing a combination of the markers most commonly associated with HAND may help delineate the mechanisms of HAND.

Higher CSF Ferritin Heavy-Chain (Fth1) and Transferrin Predict Better Neurocognitive Performance in People with HIV.

HIV-associated neurocognitive disorder (HAND) remains prevalent despite antiretroviral therapy and involves white matter damage in the brain. Although iron is essential for myelination and myelin maintenance/repair, its role in HAND is largely unexplored. We tested the hypotheses that cerebrospinal fluid (CSF) heavy-chain ferritin (Fth1) and transferrin, proteins integral to iron delivery and myelination, are associated with neurocognitive performance in people with HIV (PWH). Fth1, transferrin, and the pro-inflammatory cytokines TNF-α and IL-6 were quantified in CSF at baseline (entry) in 403 PWH from a prospective observational study who underwent serial, comprehensive neurocognitive assessments. Associations of Fth1 and transferrin with Global Deficit Score (GDS)-defined neurocognitive performance at baseline and 30-42 months of follow-up were evaluated by multivariable regression. While not associated with neurocognitive performance at baseline, higher baseline CSF Fth1 predicted significantly better neurocognitive performance over 30 months in all PWH (p < 0.05), in PWH aged < 50 at 30, 36, and 42 months (all p < 0.05), and in virally suppressed PWH at all three visit time-points (all p < 0.01). Higher CSF transferrin was associated with superior neurocognitive performance at all visits, primarily in viremic individuals (all p < 0.05). All associations persisted after adjustment for neuro-inflammation. In summary, higher CSF Fth1 is neuroprotective over prolonged follow-up in all and virally suppressed PWH, while higher CSF transferrin may be most neuroprotective during viremia. We speculate that higher CSF levels of these critical iron-delivery proteins support improved myelination and consequently, neurocognitive performance in PWH, providing a rationale for investigating their role in interventions to prevent and/or treat HAND.

Beta amyloid levels in cerebrospinal fluid of HIV-infected people vary by exposure to antiretroviral therapy.

BACKGROUND: HIV-associated neurocognitive disorders (HAND) persist despite the widespread implementation of combined antiretroviral therapy (ART). As people with HIV (PWH) age on ART regimens, the risk of age-related comorbidities, such as Alzheimer's disease may increase. However, questions remain as to whether HIV or ART will alter such risks. Beta amyloid (Aß) and phosphorylated-tau (p-tau) proteins are associated with Alzheimer's disease and their levels are altered in the CSF of Alzheimer's disease cases. METHODS: To better understand how these Alzheimer's disease-related markers are affected by HIV infection and ART, postmortem CSF collected from 70 well characterized HIV+ decedents was analyzed for Aß1-42, Aß1-40, and p-tau levels. RESULTS: Aß1-42 and Aß1-40 CSF levels were higher in cases that were exposed to ART. Aß1-42 and Aß1-40 CSF levels were also higher in cases on protease inhibitors compared with those with no exposure to protease inhibitors. Aß1-42 and Aß1-40 levels in CSF were lowest in HIV+ cases with HIV-associated dementia (HAD) and levels were highest in those diagnosed with asymptomatic neurocognitive impairment (ANI) and minor neurocognitive disorder (MND). Aß1-42 and Aß1-40 were inversely related with p-tau levels in all cases, as previously reported. CONCLUSION: These data suggest that ART exposure is associated with increased levels of Aß1-42 and Aß1-40 in the CSF. Also, HAD, but not ANI/MND diagnosis is associated with decreased levels of Aß1-42 and Aß1-40 in CSF, potentially suggesting impaired clearance. These data suggest that HIV infection and ART may impact pathogenic mechanisms involving Aß1-42 and Aß1-40, but not p-tau.

Aging, comorbidities, and the importance of finding biomarkers for HIV-associated neurocognitive disorders.

HIV-associated neurocognitive disorders (HAND) continue to affect a large proportion of persons living with HIV despite effective viral suppression with combined antiretroviral therapy (cART). Importantly, milder versions of HAND have become more prevalent. The pathogenesis of HAND in the era of cART appears to be multifactorial with contributions from central nervous system (CNS) damage that occur prior to starting cART, chronic immune activation, cART neurotoxicity, and various age-related comorbidities (i.e., cardiovascular and cerebrovascular disease, diabetes, hyperlipidemia). Individuals with HIV may experience premature aging, which could also contribute to cognitive impairment. Likewise, degenerative disorders aside from HAND increase with age and there is evidence of shared pathology between HAND and other neurodegenerative diseases, such as Alzheimer's disease, which can occur with or without co-existing HAND. Given the aforementioned complex interactions associated with HIV, cognitive impairment, and aging, it is important to consider an age-appropriate differential diagnosis for HAND as the HIV-positive population continues to grow older. These factors make the accuracy and reliability of the diagnosis of mild forms of HAND in an aging population of HIV-infected individuals challenging. The complexity of current diagnosis of mild HAND also highlights the need to develop reliable biomarkers. Ultimately, the identification of a set of specific biomarkers will be required to achieve early and accurate diagnosis, which will be necessary assuming specific treatments for HAND are developed.

Cerebrospinal Fluid Concentrations of the Synaptic Marker Neurogranin in Neuro-HIV and Other Neurological Disorders.

PURPOSE OF REVIEW: The aim of this study was to examine the synaptic biomarker neurogranin in cerebrospinal fluid (CSF) in different stages of HIV infection and in relation to what is known about CSF neurogranin in other neurodegenerative diseases. RECENT FINDINGS: CSF concentrations of neurogranin are increased in Alzheimer's disease, but not in other neurodegenerative disorder such as Parkinson's disease, frontotemporal dementia, and Lewy body dementia. Adults with HIV-associated dementia have been found to have decreased levels of neurogranin in the frontal cortex, which at least to some extent, may be mediated by the proinflammatory cytokines IL-1ß and IL-8. CSF neurogranin concentrations were in the same range for all groups of HIV-infected individuals and uninfected controls. This either indicates that synaptic injury is not an important part of HIV neuropathogenesis or that CSF neurogranin is not sensitive to the type of synaptic impairment present in HIV-associated neurocognitive disorders.

Diagnostic and prognostic biomarkers for HAND.

In 2007, the nosology for HIV-1-associated neurocognitive disorders (HAND) was updated to a primarily neurocognitive disorder. However, currently available diagnostic tools lack the sensitivity and specificity needed for an accurate diagnosis for HAND. Scientists and clinicians, therefore, have been on a quest for an innovative biomarker to diagnose (i.e., diagnostic biomarker) and/or predict (i.e., prognostic biomarker) the progression of HAND in the post-combination antiretroviral therapy (cART) era. The present review examined the utility and challenges of four proposed biomarkers, including neurofilament light (NFL) chain concentration, amyloid (i.e., sAPPα, sAPPß, amyloid ß) and tau proteins (i.e., total tau, phosphorylated tau), resting-state functional magnetic resonance imaging (fMRI), and prepulse inhibition (PPI). Although significant genotypic differences have been observed in NFL chain concentration, sAPPα, sAPPß, amyloid ß, total tau, phosphorylated tau, and resting-state fMRI, inconsistencies and/or assessment limitations (e.g., invasive procedures, lack of disease specificity, cost) challenge their utility as a diagnostic and/or prognostic biomarker for milder forms of neurocognitive impairment (NCI) in the post-cART era. However, critical evaluation of the literature supports the utility of PPI as a powerful diagnostic biomarker with high accuracy (i.e., 86.7-97.1%), sensitivity (i.e., 89.3-100%), and specificity (i.e., 79.5-94.1%). Additionally, the inclusion of multiple CSF and/or plasma markers, rather than a single protein, may provide a more sensitive diagnostic biomarker for HAND; however, a pressing need for additional research remains. Most notably, PPI may serve as a prognostic biomarker for milder forms of NCI, evidenced by its ability to predict later NCI in higher-order cognitive domains with regression coefficients (i.e., r) greater than 0.8. Thus, PPI heralds an opportunity for the development of a brief, noninvasive diagnostic and promising prognostic biomarker for milder forms of NCI in the post-cART era.

The current understanding of overlap between characteristics of HIV-associated neurocognitive disorders and Alzheimer's disease.

The advent of effective antiretroviral medications (ARVs) has led to an aging of the HIV population with approximately 50% of people with HIV (PWH) being over the age of 50 years. Neurocognitive complications, typically known as HIV-associated neurocognitive disorders (HAND), persist in the era of ARVs and, in addition to risk of HAND, older PWH are also at risk for age-associated, neurodegenerative disorders including Alzheimer's disease (AD). It has been postulated that risk for AD may be greater among PWH due to potential compounding effects of HIV and aging on mechanisms of neural insult. We are now faced with the challenge of disentangling AD from HAND, which has important prognostic and treatment implications given the more rapidly debilitating trajectory of AD. Herein, we review the evidence to date demonstrating both parallels and differences in the profiles of HAND and AD. We specifically address similarities and difference of AD and HAND as it relates to (1) neuropsychological profiles (cross-sectional/longitudinal), (2) AD-associated neuropathological features as evidenced from neuropathological, cerebrospinal fluid and neuroimaging assessments, (3) biological mechanisms underlying cortical amyloid deposition, (4) parallels in mechanisms of neural insult, and (5) common risk factors. Our current understanding of the similarities and dissimilarities of AD and HAND should be further delineated and leveraged in the development of differential diagnostic methods that will allow for the early identification of AD and more suitable and effective treatment interventions among graying PWH.

Vitamin D is not associated with HIV-associated neurocognitive disorder in Rakai, Uganda.

We investigated whether vitamin D is associated with HIV-associated neurocognitive disorder (HAND). HIV-infected (HIV+) antiretroviral therapy (ART)-naïve adults in rural Uganda underwent a neurocognitive battery for determination of HAND stage at baseline and after 2 years. Baseline serum 25-hydroxyvitamin D (25OH-D) and serum and cerebrospinal fluids (CSF) vitamin D-binding protein (VDBP) were obtained. Of the 399 participants, 4% (n = 16) were vitamin D deficient (25OH-D < 20 ng/mL). There was no association between 25OH-D, serum or CSF VDBP, and HAND stage at baseline or follow-up. Future studies in a population with higher levels of vitamin D deficiency may be warranted.

CSF concentrations of soluble TREM2 as a marker of microglial activation in HIV-1 infection.

Objective: To explore changes in CSF sTREM2 concentrations in the evolving course of HIV-1 infection. Methods: In this retrospective cross-sectional study, we measured concentrations of the macrophage/microglial activation marker sTREM2 in CSF samples from 121 HIV-1-infected adults and 11 HIV-negative controls and examined their correlations with other CSF and blood biomarkers of infection, inflammation, and neuronal injury. Results: CSF sTREM2 increased with systemic and CNS HIV-1 disease severity, with the highest levels found in patients with HIV-associated dementia (HAD). In untreated HIV-1-infected patients without an HAD diagnosis, levels of CSF sTREM2 increased with decreasing CD4+ T-cell counts. CSF concentrations of both sTREM2 and the neuronal injury marker neurofilament light protein (NFL) were significantly associated with age. CSF sTREM2 levels were also independently correlated with CSF NFL. Notably, this association was also observed in HIV-negative controls with normal CSF NFL. HIV-infected patients on suppressive antiretroviral treatment had CSF sTREM2 levels comparable to healthy controls. Conclusions: Elevations in CSF sTREM2 levels, an indicator of macrophage/microglial activation, are a common feature of untreated HIV-1 infection that increases with CD4+ T-cell loss and reaches highest levels in HAD. The strong and independent association between CSF sTREM2 and CSF NFL suggests a linkage between microglial activation and neuronal injury in HIV-1 infection. CSF sTREM2 has the potential of being a useful biomarker of innate CNS immune activation in different stages of untreated and treated HIV-1 infection.

Transient and asymptomatic meningitis in human immunodeficiency virus-1 subtype C: a case study of genetic compartmentalization and biomarker dynamics.

Human immunodeficiency virus (HIV) genetic compartmentalization is defined as genetic differences in HIV in different tissue compartments or subcompartments that characterize viral quasispecies. This descriptive, longitudinal study assessed the dynamics of inflammation, humoral immune response, blood-brain barrier, blood-cerebrospinal fluid (CSF) barrier, as well as neuronal injury biomarkers in serially obtained CSF and serum samples from an antiretroviral (ARV) therapy-naïve patient with HIV-1 subtype C with CSF HIV genetic compartmentalization that resolved spontaneously without ARV treatment. The first CSF sample showed an increase in white blood cell (WBC) count (382 cells/mm3) and a marked increase in the levels of inflammatory cytokines and chemokines, including tumor necrosis factor (TNF)α, interleukin (IL)-10, IP-10, and regulated on activation, normal T cell expressed and secreted (RANTES), which raise the suspicion of dual infection. Serum sample analysis showed all cytokine levels to be normal, with only IP-10 slightly increased. These results corroborate the hypothesis that the CNS immunologic response in a patient with HIV infection was independent of the systemic immunologic response. The patient also had persistently elevated levels of sCD14, neopterin, and ß2M, which were strongly suggestive of persistent CNS immunologic stimulation. This report describes a patient with HIV subtype C who developed a transient episode of asymptomatic HIV meningitis with compartmentalization of HIV in the CSF that resolved independently of ARV therapy. Extensive CSF studies were performed as part of an ongoing longitudinal study, which revealed CNS immune abnormalities. This case presents evidence of HIV-1 subtype C neurotropism and compartmentalization.

Peripheral and cerebrospinal fluid immune activation and inflammation in chronically HIV-infected patients before and after virally suppressive combination antiretroviral therapy (cART).

Cerebrospinal fluid (CSF)/plasma HIV-RNA ratio has been associated with residual neurocognitive impairment on cART, leading us to hypothesize a specific peripheral and/or CSF immune feature in patients with high CSF/plasma ratio (≥ 1). In patients with diverse pre-cART CSF/plasma ratio (61/70 with CSF/plasma ratio < 1, L-CSF, 9/70 with CSF/plasma ratio ≥ 1, H-CSF), we investigated the effects of 12 months of effective cART on peripheral and CSF inflammatory markers, on T cell activation/maturation and HIV/CMV-specific intracellular cytokine pattern. We also studied the possible clinical association between peripheral/CSF pro-inflammatory milieu and neurocognitive screening tests (MMSE, FAB, IHDS). Prior to cART, the two groups were comparable for peripheral and CSF inflammation, T cell activation/proliferation and maturation, and HIV/CMV-specific response. Upon cART initiation, both H-CSF and L-CSF featured a significant reduction in plasma TNF-α and circulating CD8 activation, with a redistribution of memory/naïve T cell subsets in L-CSF alone. In the CSF compartment, cART seemed able to reduce pro-inflammatory cytokine/chemokine levels in both H-CSF and L-CSF patients. Interestingly, despite a reduction in the pro-inflammatory milieu, no changes were shown in neurocognitive screening tests in both patients' groups. We hereby show that 12-month cART is able to reduce intratechal and peripheral pro-inflammatory burden; a longer cART exposure and a more comprehensive neuropsychological evaluation might be necessary to gain a broader insight into the possible effects on neurocognitive performance.

HIV, prospective memory, and cerebrospinal fluid concentrations of quinolinic acid and phosphorylated Tau.

There is mounting evidence that prospective memory (PM) is impaired during HIV infection despite treatment. In this prospective study, 66 adults (43 HIV+ and 23 HIV negative) underwent PM assessment and cerebrospinal fluid (CSF) examination. HIV+ participants had significantly lower PM but significantly higher CSF concentrations of CXCL10 and quinolinic acid (QUIN). Higher CSF phosphorylated Tau (pTau) was associated with worse PM. In a secondary analysis excluding outliers, higher QUIN correlated with higher pTau. CSF QUIN is thus elevated during HIV infection despite antiretroviral therapy and could indirectly contribute to impaired PM by influencing the formation of pTau.

Cerebrospinal fluid cell-free mitochondrial DNA is associated with HIV replication, iron transport, and mild HIV-associated neurocognitive impairment.

BACKGROUND: Mitochondria are abundant organelles critical for energy metabolism and brain function. Mitochondrial DNA (mtDNA), released during cellular injury and as part of the innate immune response to viral pathogens, contains CpG motifs that act as TLR-9 ligands. We investigated relationships between cerebrospinal fluid (CSF) cell-free mtDNA levels and HIV viral load (VL), biomarkers of inflammation and iron transport, and neurocognitive (NC) function in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort. METHODS: We quantified cell-free mtDNA in CSF by droplet digital PCR in 332 CHARTER participants who underwent comprehensive neuropsychiatric evaluation. NC performance was assessed using the global deficit score (GDS) as either a continuous or a binary measure (GDS ≥ 0.5, impaired vs. GDS < 0.5, unimpaired). CSF, clinical, and biomarker data from the earliest available time point were analyzed. Cell-free mtDNA associations with CSF inflammation and iron-related biomarkers [CXCL10, IL-6, IL-8, TNF-a, transferrin (TF), ceruloplasmin (CP), and vascular endothelial growth factor (VEGF)], VL, and GDS were evaluated by multivariable regression. RESULTS: CSF cell-free mtDNA levels were significantly lower in participants with undetectable (vs. detectable) VL in either plasma (p < 0.001) or CSF (p < 0.001) and in those on antiretroviral therapy (ART; p < 0.001). Participants on ART with undetectable VL in both CSF and plasma had lower mtDNA levels than those with detectable VL in both compartments (p = 0.001). Higher mtDNA levels were observed in participants in the highest vs. lowest tertile (T3 vs. T1) of CSF CXCL10 (T3 vs. T1, p < 0.001) and TNF-a (T3 vs. T1, p < 0.05) in unadjusted analyses. MtDNA levels also correlated with CSF leukocyte count. After adjusting for CSF leukocyte count and VL, mtDNA levels were also associated with other inflammation- and iron-related biomarkers in CSF, including TF (T3 vs. T1, p < 0.05) and CP (T3 vs. T1, p < 0.05). With additional correction for ART use, mtDNA was also negatively associated with CSF VEGF (p < 0.05) and IL-6 (p = 0.05). We observed no associations of CSF mtDNA levels with age or GDS-defined NC impairment. CONCLUSIONS: CSF cell-free mtDNA levels were associated with HIV RNA and ART status, as well as with biomarkers of iron transport and VEGF, a growth factor with known effects on mitochondrial integrity and autophagy. CSF mtDNA may be a biomarker of iron dysregulation and/or neuroinflammation during HIV infection.

Cerebrospinal fluid interferon alpha levels correlate with neurocognitive impairment in ambulatory HIV-Infected individuals.

HIV-associated neurocognitive disorders (HANDs) continue to be common and are associated with increased morbidity and mortality. However, the underlying mechanisms in the combination antiretroviral therapy (cART) era are not fully understood. Interferon alpha (IFNα) is an antiviral cytokine found to be elevated in the cerebrospinal fluid (CSF) of individuals with advanced HIV-associated dementia in the pre-cART era. In this cross-sectional study, we investigated the association between IFNα and neurocognitive performance in ambulatory HIV-infected individuals with milder impairment. An eight-test neuropsychological battery representing six cognitive domains was administered. Individual scores were adjusted for demographic characteristics, and a composite neuropsychological score (NPT-8) was calculated. IFNα and CSF neurofilament light chain (NFL) levels were measured using enzyme-linked immunosorbent assay (ELISA). There were 15 chronically infected participants with a history of significant immunocompromise (median nadir CD4+ of 49 cells/µl). Most participants were neurocognitively impaired (mean global deficit score of 0.86). CSF IFNα negatively correlated with three individual tests (Trailmaking A, Trailmaking B, and Stroop Color-Word) as well as the composite NPT-8 score (r = -0.67, p = 0.006). These negative correlations persisted in multivariable analyses adjusting for chronic hepatitis B and C. Additionally, CSF IFNα correlated strongly with CSF NFL, a marker of neuronal damage (rho = 0.748, p = 0.0013). These results extend findings from individuals with severe HIV-associated dementia in the pre-cART era and suggest that IFNα may continue to play a role in HAND pathogenesis during the cART era. Further investigation into the role of IFNα is indicated.

Cerebrospinal fluid biomarkers and HIV-associated neurocognitive disorders in HIV-infected individuals in Rakai, Uganda.

In the USA, increased cerebrospinal fluid (CSF) inflammatory cytokines have been observed in antiretroviral therapy (ART)-naive, HIV-seropositive individuals with HIV-associated neurocognitive disorder (HAND). We characterized the relationship between HAND and CSF biomarker expression in ART-naive, HIV-seropositive individuals in Rakai, Uganda. We analyzed CSF of 78 HIV-seropositive, ART-naive Ugandan adults for 17 cytokines and 20 neurodegenerative biomarkers via Luminex multiplex assay. These adults underwent neurocognitive assessment to determine their degree of HAND. We compared biomarker concentrations between high and low CD4 groups and across HAND classifications, adjusting for multiple comparisons. Individuals with CD4 <200 cells/µL (N = 38) had elevated levels of CSF Interleukin (IL)-2, IL-12, granulocyte-macrophage colony-stimulating factor (GM-CSF), TNF-α, matrix metalloproteinase (MMP)-1, MMP-7, and S100 calcium-binding protein B (S100B) and lower levels of amyloid ß42. Individuals with CD4 351-500 cells/µL (N = 40) had significantly higher CSF levels of interleukin (IL)-1ß, amyloid ß42, and soluble receptor for advanced glycation end products (sRAGE). Increasing levels of S100B, platelet-derived growth factor-AA (PDGF-AA), brain-derived neurotrophic factor (BDNF), and sRAGE were associated with decreased odds of mild neurocognitive disorder (n = 22) or HIV-associated dementia (n = 15) compared with normal function (n = 30) or asymptomatic neurocognitive impairment (n = 11). Increased levels of interferon (IFN)-γ were associated with increased odds of mild neurocognitive impairment or HIV-associated dementia relative to normal or asymptomatic neurocognitive impairment. Proinflammatory CSF cytokines, chemokines, and neurodegenerative biomarkers were present in increasing concentrations with advanced immunosuppression and may play a role in the development of HAND. The presence of select CNS biomarkers may also play a protective role in the development of HAND.

HIV/neuroAIDS biomarkers.

HIV infection often causes neurological symptoms including cognitive and motor dysfunction, which have been collectively termed HIV/neuroAIDS. Neuropsychological assessment and clinical symptoms have been the primary diagnostic criteria for HIV/neuroAIDS, even for the mild cognitive and motor disorder, the most prevalent form of HIV/neuroAIDS in the era of combination antiretroviral therapy. Those performance-based assessments and symptoms are generally descriptive and do not have the sensitivity and specificity to monitor the diagnosis, progression, and treatment response of the disease when compared to objective and quantitative laboratory-based biological markers, or biomarkers. In addition, effects of demographics and comorbidities such as substance abuse, psychiatric disease, nutritional deficiencies, and co-infection on HIV/neuroAIDS could be more readily determined using biomarkers than using neuropsychological assessment and clinical symptoms. Thus, there have been great efforts in identification of HIV/neuroAIDS biomarkers over the past two decades. The need for reliable biomarkers of HIV/neuroAIDS is expected to increase as the HIV-infected population ages and their vulnerability to neurodegenerative diseases, particularly Alzheimer's disease increases. Currently, three classes of HIV/neuroAIDS biomarkers are being pursued to establish objective laboratory-based definitions of HIV-associated neurologic injury: cerebrospinal fluid biomarkers, blood biomarkers, and neuroimaging biomarkers. In this review, we will focus on the current knowledge in the field of HIV/neuroAIDS biomarker discovery.