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Central nervous system (CNS) immune activation is an important driver of neuronal injury during several neurodegenerative and neuroinflammatory diseases. During HIV infection, CNS immune activation is associated with high rates of neurocognitive impairment, even during sustained long-term suppressive antiretroviral therapy (ART). However, the cellular subsets that drive immune activation and neuronal damage in the CNS during HIV infection and other neurological conditions remain unknown, in part because CNS cells are difficult to access in living humans. Using single-cell RNA sequencing (scRNA-seq) on cerebrospinal fluid (CSF) and blood from adults with and without HIV, we identified a rare (

Using the Olink Explore 1536 platform, we measured 1,463 unique proteins in 303 cerebrospinal fluid (CSF) specimens from four clinical centers contributed by uninfected controls and 12 groups of people living with HIV-1 infection representing the spectrum of progressive untreated and treated chronic infection. We present three initial analyses of these measurements: an overview of the CSF protein features of the sample; correlations of the CSF proteins with CSF HIV-1 RNA and neurofilament light chain protein (NfL) concentrations; and comparison of CSF proteins in HIV-associated dementia (HAD) and neurosymptomatic CSF escape (NSE). These reveal a complex but coherent picture of CSF protein changes with highest concentrations of many proteins during CNS injury in the HAD and NSE groups and variable protein changes across the course of systemic HIV-1 progression that included two common patterns, designated as lymphoid and myeloid patterns, related to principal involvement of their underlying inflammatory cell lineages. Antiretroviral therapy reduced CSF protein perturbations, though not always to control levels. The dataset of these CSF protein measurements, along with background clinical information, is posted online. Extended studies of this unique dataset will supplement this report to provide more detailed characterization of the dynamic impact of HIV-1 infection on the CSF proteome across the spectrum of HIV-1 infection, advancing the mechanistic understanding of HIV-1-related CNS pathobiology. Author summary: We measured more than 1,400 proteins in 303 cerebrospinal fluid (CSF) specimens from a representative broad range of untreated and treated people living with HIV-1 infection (PLWH) along with uninfected controls who volunteered for our studies. The results defined a complex, but generally coherent set of changes in many immune-inflammatory proteins and several central nervous system injury biomarkers as systemic HIV-1 infection progressed. There was a marked increase in many of these protein biomarkers in individuals with HIV-associated dementia and neurosymptomatic CSF viral escape, two conditions distinguished by overt, and characteristically severe, neurological impairment. The resultant data and initial analyses advance the characterization and understanding of the evolution of HIV-driven neuropathogenesis. The large dataset from this study is posted online and available to other investigators for further analyses, extending the utility of these data and potentially aiding in developing future prevention, diagnosis and mitigation of the deleterious impact of HIV-1 infection on the brain. [ABSTRACT FROM AUTHOR]

The central nervous system (CNS) is an important target of HIV, and cerebrospinal fluid (CSF) can provide a window into host-virus interactions within the CNS. The goal of this study was to determine whether HIV-specific CD8(+) T cells are present in CSF of HIV controllers (HC), who maintain low to undetectable plasma viremia without antiretroviral therapy (ART). CSF and blood were sampled from 11 HC, defined based on plasma viral load (VL) consistently below 2,000 copies/ml without ART. These included nine elite controllers (EC, plasma VL 10,000 copies/ml, no ART); seven individuals with viremia suppressed due to ART (Tx, VL

ObjectiveLittle is known about the extent of cortical and subcortical volumetric alterations that may occur within the first year of HIV infection [primary HIV infection (PHI)].DesignWe used structural MRI in this prospective cross-sectional neuroimaging study to determine the extent of volumetric changes in early HIV infection.MethodsCerebrospinal fluid, blood, neuropsychological testing, and structural T1 MRI scans were acquired from 18 HIV and 47 PHI age-matched antiretroviral-naïve male participants. Using FreeSurfer 5.1, volumetric measurements were obtained from the caudate, amygdala, corpus callosum, ventricles, putamen, thalamus, cortical white matter, and total gray matter. Regional volumes were compared groupwise and related to biomarkers in cerebrospinal fluid (viral load, neopterin, and neurofilament light chain), blood (viral load, CD4, and CD8 T-cell count), and neuropsychometric tests (digit-symbol, grooved pegboard, finger-tapping, and timed gait).ResultsA trend-level moderate reduction of putamen volume (P = 0.076, adjusted Cohen's d = 0.5 after controlling for age) was observed for PHI compared with HIV-uninfected individuals. Within the PHI group, putamen volume associated with CD4 cell count (P = 0.03), CD4/CD8 ratio (P = 0.045), infection duration (P = 0.009), and worsening psychomotor performance on the digit-symbol (P = 0.028), finger-tapping (P = 0.039), and timed gait (P = 0.009) tests.ConclusionOur volumetric results suggest that the putamen is preferentially susceptible to early HIV-associated processes. Examining the natural course of early HIV infection longitudinally will allow for mapping of the trajectory of HIV-associated central nervous system changes, enabling creation of improved interventional strategies to potentially stabilize or reverse these observed structural changes.

BackgroundLimited data exist comparing viral quasispecies between cerebrospinal fluid (CSF) and plasma compartments during primary HIV infection. Deep sequencing is a new method to examine the HIV plasma and CSF quasispecies.MethodsIn this pilot study, deep sequencing of protease (PR) and reverse transcriptase (RT) was performed in plasma and CSF from participants during primary HIV infection. Estimated mutational load was calculated by mutant variant frequency multiplied by HIV-RNA level.ResultsPaired plasma and CSF samples were studied from five antiretroviral therapy-naïve male participants with median 109 days post estimated transmission, age 32 years, CD4 cell count 580 cells/μL, HIV-RNA 5.18 log10 copies/mL in plasma and 3.67 log10 copies/mL in CSF. Plasma samples averaged 7,124 reads of PR and 2,448 reads of RT, whereas CSF samples averaged 7,082 and 2,792 reads, respectively. A distinct drug-resistance pattern with linked mutations present at significant levels (5-10%) was detected in one participant in CSF. Other low abundance variants (>0.2%) were detected in plasma and CSF of four out of five participants.ConclusionsDeep sequencing of CSF HIV is technically possible with sufficient HIV-RNA levels. Differences between the quasispecies in the two compartments detected in one participant, which were present with a high mutational load in CSF at an estimated 3.6 months after HIV infection, suggest that early CNS compartmentalisation may be revealed by sensitive deep-sequencing methods. The presence of distinct low abundance (

Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system (CNS) begins early in systemic infection and continues throughout its untreated course. Despite a common cerebrospinal fluid inflammatory response, it is usually neurologically asymptomatic for much of this course, but can evolve in some individuals to HIV-associated dementia (HAD), a severe encephalopathy with characteristic cognitive and motor dysfunction. While widespread use of combination antiretroviral therapy (ART) has led to a marked decline in both the CNS infection and its neurologic severe consequence, HAD continues to afflict individuals presenting with advanced systemic infection in the developed world and a larger number in resource-poor settings where ART is more restricted. Additionally, milder CNS injury and dysfunction have broader prevalence, including in those treated with ART. Here we review the history and evolving nomenclature of HAD, its viral pathogenesis, clinical presentation and diagnosis, and treatment.

The character of central nervous system (CNS) HIV infection and its effects on neuronal integrity vary with evolving systemic infection. Using a cross-sectional design and archived samples, we compared concentrations of cerebrospinal fluid (CSF) neuronal biomarkers in 143 samples from 8 HIV-infected subject groups representing a spectrum of untreated systemic HIV progression and viral suppression: primary infection; four groups of chronic HIV infection neuroasymptomatic (NA) subjects defined by blood CD4+ T cells of >350, 200-349, 50-199, and

In order to characterize the cellular composition of cerebrospinal fluid (CSF) in a healthy state and in the setting of chronic pleocytosis associated with HIV-1 (HIV) infection, multi-parameter flow cytometry was used to identify and quantitate cellular phenotypes in CSF derived from HIV-uninfected healthy controls and HIV-infected subjects across a spectrum of disease and treatment. CD4+ T cells were the most frequent CSF population and the CD4:CD8 ratio was significantly increased in the CSF compared to blood (p = 0.0232), suggesting preferential trafficking of CD4+ over CD8+ T cells to this compartment. In contrast, in HIV-infection, CD8+ T cells were the major cellular component of the CSF and were markedly increased compared to HIV-uninfected subjects (p

Abstract Background Central nervous system (CNS) infection is a nearly universal feature of untreated systemic HIV infection with a clinical spectrum that ranges from chronic asymptomatic infection to severe cognitive and motor dysfunction. Analysis of cerebrospinal fluid (CSF) has played an important part in defining the character of this evolving infection and response to treatment. To further characterize CNS HIV infection and its effects, we applied advanced high-throughput proteomic methods to CSF to identify novel proteins and their changes with disease progression and treatment. Results After establishing an accurate mass and time (AMT) tag database containing 23,141 AMT tags for CSF peptides, we analyzed 91 CSF samples by LC-MS from 12 HIV-uninfected and 14 HIV-infected subjects studied in the context of initiation of antiretroviral therapy and correlated abundances of identified proteins a) within and between subjects, b) with all other proteins across the entire sample set, and c) with "external" CSF biomarkers of infection (HIV RNA), immune activation (neopterin) and neural injury (neurofilament light chain protein, NFL). We identified a mean of 2,333 +/- 328 (SD) peptides covering 307 +/-16 proteins in the 91 CSF sample set. Protein abundances differed both between and within subjects sampled at different time points and readily separated those with and without HIV infection. Proteins also showed inter-correlations across the sample set that were associated with biologically relevant dynamic processes. One-hundred and fifty proteins showed correlations with the external biomarkers. For example, using a threshold of cross correlation coefficient (Pearson's) ≤ -0.3 and ≥0.3 for potentially meaningful relationships, a total of 99 proteins correlated with CSF neopterin (43 negative and 56 positive correlations) and related principally to neuronal plasticity and survival and to innate immunity. Pathway analysis defined several networks connecting the identified proteins, including one with amyloid precursor protein as a central node. Conclusions Advanced CSF proteomic analysis enabled the identification of an array of novel protein changes across the spectrum of CNS HIV infection and disease. This initial analysis clearly demonstrated the value of contemporary state-of-the-art proteomic CSF analysis as a discovery tool in HIV infection with likely similar application to other neurological inflammatory and degenerative diseases.

Abstract Background Minocycline is a tetracycline antibiotic that has been shown to attenuate central nervous system (CNS) lentivirus infection, immune activation, and brain injury in model systems. To initiate assessment of minocycline as an adjuvant therapy in human CNS HIV infection, we conducted an open-labelled pilot study of its effects on cerebrospinal fluid (CSF) and blood biomarkers of infection and immune responses in 7 viremic subjects not taking antiretroviral therapy. Results There were no discernable effects of minocycline on CSF or blood HIV-1 RNA, or biomarkers of immune activation and inflammation including: CSF and blood neopterin, CSF CCL2, CSF white blood cell count, and expression of cell-surface activation markers on CSF and blood T lymphocytes and monocytes. Conclusions This pilot study of biological responses to minocycline suggests little potential for its use as adjunctive antiviral or immunomodulating therapy in chronic untreated HIV infection.

BackgroundCentral nervous system (CNS) exposure to HIV is a universal facet of systemic infection. Because of its proximity to and shared barriers with the brain, cerebrospinal fluid (CSF) provides a useful window into and model of human CNS HIV infection.MethodsProspective study of the relationships of CSF to plasma HIV RNA, and the effects of: 1) progression of systemic infection, 2) CSF white blood cell (WBC) count, 3) antiretroviral therapy (ART), and 4) neurological performance. One hundred HIV-infected subjects were cross-sectionally studied, and 28 were followed longitudinally after initiating or changing ART.ResultsIn cross-sectional analysis, HIV RNA levels were lower in CSF than plasma (median difference 1.30 log10 copies/mL). CSF HIV viral loads (VLs) correlated strongly with plasma VLs and CSF WBC counts. Higher CSF WBC counts associated with smaller differences between plasma and CSF HIV VL. CSF VL did not correlate with blood CD4 count, but CD4 counts

Abstract Background Minocycline is a tetracycline antibiotic that has been shown to attenuate central nervous system (CNS) lentivirus infection, immune activation, and brain injury in model systems. To initiate assessment of minocycline as an adjuvant therapy in human CNS HIV infection, we conducted an open-labelled pilot study of its effects on cerebrospinal fluid (CSF) and blood biomarkers of infection and immune responses in 7 viremic subjects not taking antiretroviral therapy. Results There were no discernable effects of minocycline on CSF or blood HIV-1 RNA, or biomarkers of immune activation and inflammation including: CSF and blood neopterin, CSF CCL2, CSF white blood cell count, and expression of cell-surface activation markers on CSF and blood T lymphocytes and monocytes. Conclusions This pilot study of biological responses to minocycline suggests little potential for its use as adjunctive antiviral or immunomodulating therapy in chronic untreated HIV infection.

Abstract Background Central nervous system (CNS) exposure to HIV is a universal facet of systemic infection. Because of its proximity to and shared barriers with the brain, cerebrospinal fluid (CSF) provides a useful window into and model of human CNS HIV infection. Methods Prospective study of the relationships of CSF to plasma HIV RNA, and the effects of: 1) progression of systemic infection, 2) CSF white blood cell (WBC) count, 3) antiretroviral therapy (ART), and 4) neurological performance. One hundred HIV-infected subjects were cross-sectionally studied, and 28 were followed longitudinally after initiating or changing ART. Results In cross-sectional analysis, HIV RNA levels were lower in CSF than plasma (median difference 1.30 log10 copies/mL). CSF HIV viral loads (VLs) correlated strongly with plasma VLs and CSF WBC counts. Higher CSF WBC counts associated with smaller differences between plasma and CSF HIV VL. CSF VL did not correlate with blood CD4 count, but CD4 counts In subjects starting ART, those with lower CD4 counts had slower initial viral decay in CSF than in plasma. In all subjects, including five with persistent plasma viremia and four with new-onset ADC, CSF HIV eventually approached or reached the limit of viral detection and CSF pleocytosis resolved. Conclusion CSF HIV infection is common across the spectrum of infection and is directly related to CSF pleocytosis, though whether the latter is a response to or a contributing cause of CSF infection remains uncertain. Slowing in the rate of CSF response to ART compared to plasma as CD4 counts decline indicates a changing character of CSF infection with systemic immunological progression. Longer-term responses indicate that CSF infection generally responds well to ART, even in the face of systemic virological failure due to drug resistance. We present simple models to explain the differing relationships of CSF to plasma HIV in these settings.

With the advent of combination antiretroviral therapies, the mortality rate from HIV has declined, while the prevalence of long-term HIV-related neurologic complications continues to rise. Thirty-six million individuals are living with HIV around the world, many of whom reside in resource-limited settings. The majority of studies have focused on individuals residing in the developed world, while the impact of HIV disproportionately affects people living in developing countries. This review focuses on recent domestic and international studies regarding neurologic complications related to HIV, including opportunistic infections, peripheral neuropathy, cerebrovascular disease, and HIV-associated neurocognitive disorders, in light of the growing population affected by these conditions. [ABSTRACT FROM AUTHOR]

The central nervous system (CNS) is an important target of HIV, and cerebrospinal fluid (CSF) can provide a window into host-virus interactions within the CNS. The goal of this study was to determine whether HIV-specific CD8+ T cells are present in CSF of HIV controllers (HC), who maintain low to undetectable plasma viremia without antiretroviral therapy (ART). CSF and blood were sampled from 11 HC, defined based on plasma viral load (VL) consistently below 2,000 copies/ml without ART. These included nine elite controllers (EC, plasma VL <40 copies/ml) and two viremic controllers (VC, VL 40-2,000 copies/ml). All controllers had CSF VL <40 copies/ml. Three comparison groups were also sampled: six HIV noncontrollers (NC, VL >10,000 copies/ml, no ART); seven individuals with viremia suppressed due to ART (Tx, VL <40 copies/ml); and nine HIV-negative controls. CD4+ and CD8+ T cells in CSF and blood were analyzed by flow cytometry to assess expression of CCR5, activation markers CD38 and HLA-DR, and memory/effector markers CD45RA and CCR7. HIV-specific CD8+ T cells were quantified by major histocompatibility complex class I multimer staining. HIV-specific CD8+ T cells were detected ex vivo at similar frequencies in CSF of HC and noncontrollers; the highest frequencies were in individuals with CD4 counts below 500 cells/μl. The majority of HIV-specific CD8+ T cells in CSF were effector memory cells expressing CCR5. Detection of these cells in CSF suggests active surveillance of the CNS compartment by HIV-specific T cells, including in individuals with long-term control of HIV infection in the absence of therapy. [ABSTRACT FROM AUTHOR]

Since the advent of combination antiretroviral therapy (cART), HIV has transformed from a fatal disease to a chronic illness that often presents with milder central nervous system (CNS) symptoms laced with related confounders. The immune recovery associated with access to cART has led to a new spectrum of immune-mediated presentations of infection, phenotypically distinct from the conditions observed in advanced disease. HIV-associated neurocognitive disorder (HAND) entails a categorized continuum of disorders reflecting an array of clinical presentation, outcome, and increasing level of severity: asymptomatic neurocognitive impairment (ANI),mild neurocognitive disorder (MND), and HIV-associated dementia (HAD). HAND is defined through an assessment of neurocognitive abilities and functional performance. Progressive neurologic symptoms detected in patients on cART with detectable CSF viral load and a suppressed plasma viral load, or CSF viral load 1 log10 greater than low detectable plasma viral load, characterize a phenomenon termed symptomatic CSF "escape." CD8+ T-cell encephalitis, possibly a form of CNS immune reconstitution inflammatory syndrome, resembles CNS "escape" as it presents in patients despite viral suppression with cART. Cerebral toxoplasmosis, cryptococcal meningitis, and progressive multifocal leukoencephalopathy, are AIDS defining conditions with associated high mortality risk. Cerebral toxoplasmosis and cryptococcal meningitis typically manifest in immunosuppressed patients (<200 CD4+ T-cells/μL), while PML can occur in patients with higher CD4+ T-cell counts. Neurologic conditions are increasingly interconnected with chronic diseases, and classic opportunistic infections may have altered phenotypes in the cART era. However, there exist promising diagnostic methods and therapeutic approaches, as well as associated pitfalls in diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Objective: To compare central nervous system (CNS) outcomes in participants treated during acute HIV infection with standard combination antiretroviral therapy (cART) vs. cART plus integrase inhibitor and CCR5 antagonist (cART+). Design: 24-week randomized open-label prospective evaluation. Method: Participants were evaluated then randomized to initiate cART (efavirenz, tenofovir, and either emtricitabine or lamivudine) vs. cART+ (cART plus raltegravir and maraviroc) during acute HIV and re-evaluated at 4, 12 and 24 weeks. We examined plasma and CSF cytokines, HIV RNA levels, neurological and neuropsychological findings, and brain MRS across groups and compared to healthy controls. Results: At baseline, 62 participants were in Fiebig stages I-V. Randomized groups were similar for mean age (27 vs. 25, p = 0.137), gender (each 94% male), plasma log10 HIV RNA (5.4 vs. 5.6, p = 0.382), CSF log10 HIV RNA (2.35 vs. 3.31, p = 0.561), and estimated duration of HIV (18 vs. 17 days, p = 0.546). Randomized arms did not differ at 24 weeks by any CNS outcome. Combining arms, all measures concurrent with antiretroviral treatment improved, for example, neuropsychological testing (mean NPZ-4 of -0.408 vs. 0.245, p<0.001) and inflammatory markers by MRS (e.g. mean frontal white matter (FWM) choline of 2.92 vs. 2.84, p = 0.045) at baseline and week 24, respectively. Plasma neopterin (p<0.001) and interferon gamma-induced protein 10 (IP-10) (p = 0.007) remained elevated in participants compared to controls but no statistically significant differences were seen in CSF cytokines compared to controls, despite individual variability among the HIV-infected group. Conclusions: A 24-week course of cART+ improved CNS related outcomes, but was not associated with measurable differences compared to standard cART. [ABSTRACT FROM AUTHOR]

The presence of quantifiable HIV RNA in cerebrospinal fluid (CSF) during antiretroviral therapy (ART) can associate with central nervous system (CNS) pathology, but the significance of RNA detected below the limit of quantification (LOQ) on a standard assay during ART remains unknown. We compared CNS parameters between individuals with CSF RNA detected below the LOQ (20 copies/mL) with those with HIV RNA not detected. Detection of CSF HIV RNA associated with decreased blood–brain barrier integrity and with decreased executive function, but not with CNS immune activation or poorer performance in overall neuropsychological testing. [ABSTRACT FROM AUTHOR]