Plasma proteomic profiling identifies CD33 as a marker of HIV control in natural infection and after therapeutic vaccination.

BACKGROUND: Biomarkers predicting the outcome of HIV-1 virus control in natural infection and after therapeutic interventions in HIV-1 cure trials remain poorly defined. The BCN02 trial (NCT02616874), combined a T-cell vaccine with romidepsin (RMD), a cancer-drug that was used to promote HIV-1 latency reversal and which has also been shown to have beneficial effects on neurofunction. We conducted longitudinal plasma proteomics analyses in trial participants to define biomarkers associated with virus control during monitored antiretroviral pause (MAP) and to identify novel therapeutic targets that can improve future cure strategies. METHODS: BCN02 was a phase I, open-label, single-arm clinical trial in early-treated, HIV infected individuals. Longitudinal plasma proteomes were analyzed in 11 BCN02 participants, including 8 participants that showed a rapid HIV-1 plasma rebound during a monitored antiretroviral pause (MAP-NC, 'non-controllers') and 3 that remained off ART with sustained plasma viremia <2000 copies/ml (MAP-C, 'controllers'). Inflammatory and neurological proteomes in plasma were evaluated and integration data analysis (viral and neurocognitive parameters) was performed. Validation studies were conducted in a cohort of untreated HIV-1+ individuals (n = 96) and in vitro viral replication assays using an anti-CD33 antibody were used for functional validation. FINDINGS: Inflammatory plasma proteomes in BCN02 participants showed marked longitudinal alterations. Strong proteome differences were also observed between MAP-C and MAP-NC, including in baseline timepoints. CD33/Siglec-3 was the unique plasma marker with the ability to discriminate between MAPC-C and MAP-NC at all study timepoints and showed positive correlations with viral parameters. Analyses in an untreated cohort of PLWH confirmed the positive correlation between viral parameters and CD33 plasma levels, as well as PBMC gene expression. Finally, adding an anti-CD33 antibody to in vitro virus cultures significantly reduced HIV-1 replication and proviral levels in T cells and macrophages. INTERPRETATION: This study indicates that CD33/Siglec-3 may serve as a predictor of HIV-1 control and as potential therapeutic tool to improve future cure strategies. FUNDING: Spanish Science and Innovation Ministry (SAF2017-89726-R and PID2020-119710RB-I00), NIH (P01-AI131568), European Commission (GA101057548) and a Grifols research agreement.

Accentuated aging associated with HIV in a Mediterranean setting occurs mainly in persons aged>70 years: a comparative cohort study (Over50 cohort).

In an ongoing Mediterranean cohort, we compared age-related conditions between 208 HIV-infected persons and 104 matched controls. ≥3 comorbidities were found in 31.0% of HIV-infected patients and 8.7% of controls. Conditions significantly more frequent among the HIV-infected population were: lipid abnormalities, cancer, osteopenia/osteoporosis, liver disease, sexual dysfunction, hearing deficit, sleep disorders, falls, cognitive complaints, being single, living alone, and being elderly at risk. HIV-infected patients aged >70 years had a significantly higher number of cardiovascular risk factors (CVRF) and comorbidities than controls. HIV-infected persons who had never smoked had a higher prevalence of CVRFs, ≥3 comorbidities, liver disease, cancer, and cognitive complaints compared to controls. Factors associated with frailty were being a man who has sex with men, ≥3 CVRFs, nadir CD470 years. The multidisciplinary assessment also revealed concerning findings in social, cognitive, and functional variables among HIV-infected individuals, with a higher prevalence of elderly at risk than among controls.

NEU Screen Shows High Accuracy in Detecting Cognitive Impairment in Older Persons Living With HIV.

The NEUrocognitive (NEU) Screen is a practical tool proposed to screen for HIV-associated cognitive impairment in the clinical setting. This is a pencil-and-paper method that can be applied rapidly (≤10 minutes for administration) and has no copyright limitations. In this study, we aimed at investigating its diagnostic accuracy in an older population of persons living with HIV (PLWH), with cutoffs set at 30, 40, 50, and 60 years. Data were collected from a sample of 368 PLWH who underwent a comprehensive neuropsychological tests battery (gold standard). Results of statistical tests showed that accuracy of the NEU Screen increased with age of the participants. The highest degree of precision, with a sensitivity of 91% and specificity of 92%, was obtained for people ages 60 years or older (correct classification: 91%). These optimal results point to the great potential of the NEU Screen as a tool for detecting cognitive disorders in older PLWH.

Classification models for neurocognitive impairment in HIV infection based on demographic and clinical variables.

OBJECTIVE: We used demographic and clinical data to design practical classification models for prediction of neurocognitive impairment (NCI) in people with HIV infection. METHODS: The study population comprised 331 HIV-infected patients with available demographic, clinical, and neurocognitive data collected using a comprehensive battery of neuropsychological tests. Classification and regression trees (CART) were developed to obtain detailed and reliable models to predict NCI. Following a practical clinical approach, NCI was considered the main variable for study outcomes, and analyses were performed separately in treatment-naïve and treatment-experienced patients. RESULTS: The study sample comprised 52 treatment-naïve and 279 experienced patients. In the first group, the variables identified as better predictors of NCI were CD4 cell count and age (correct classification [CC]: 79.6%, 3 final nodes). In treatment-experienced patients, the variables most closely related to NCI were years of education, nadir CD4 cell count, central nervous system penetration-effectiveness score, age, employment status, and confounding comorbidities (CC: 82.1%, 7 final nodes). In patients with an undetectable viral load and no comorbidities, we obtained a fairly accurate model in which the main variables were nadir CD4 cell count, current CD4 cell count, time on current treatment, and past highest viral load (CC: 88%, 6 final nodes). CONCLUSION: Practical classification models to predict NCI in HIV infection can be obtained using demographic and clinical variables. An approach based on CART analyses may facilitate screening for HIV-associated neurocognitive disorders and complement clinical information about risk and protective factors for NCI in HIV-infected patients.

Screening for neurocognitive impairment, depression, and anxiety in HIV-infected patients in Western Europe and Canada.

CRANIum, a cross-sectional epidemiology study in Western Europe and Canada, was conducted to describe and compare the prevalence of a positive screen for neurocognitive impairment (NCI), depressive symptoms, and anxiety in an HIV-positive population either receiving combination antiretroviral therapy (cART) or who were naive to antiretroviral therapy (ART). HIV-positive patients ≥18 years of age attending a routine medical follow-up visit and able to complete the designated screening tools were eligible for study inclusion. The Brief Neurocognitive Screen was used to assess NCI; depressive and anxiety symptoms were assessed using the Hospital Anxiety and Depression Scale. The evaluable patient population (N = 2863) included 1766 men (61.7%) and 1096 (38.3%) women. A total of 1969 patients were cART-experienced (68.8%), and 894 were ART-naive (31.2%). A positive screen for NCI was found in 41.5% of patients (cART-experienced, 42.5%; ART-naive, 39.4%; p = 0.12). A positive screen for depressive symptoms was found in 15.7% of patients (cART-experienced, 16.8%; ART-naive, 13.3%; p = 0.01), whereas 33.3% of patients screened positive for anxiety (cART-experienced, 33.5%; ART-naive, 32.8%; p = 0.71). A greater percentage of women compared with men screened positive for NCI (51.78% vs. 35.1%; p < 0.0001) and depressive symptoms (17.9% vs. 14.3%; p = 0.01). These data suggest that neurocognitive and mood disorders remain highly prevalent in HIV-infected patients. Regular mental health screening in this population is warranted.

A brief and feasible paper-based method to screen for neurocognitive impairment in HIV-infected patients: the NEU screen.

OBJECTIVE: Practical screening methods are necessary to detect neurocognitive impairment (NCI) in HIV-infected patients. We aimed to find a brief and feasible paper-based tool to facilitate the diagnosis of an HIV-associated neurocognitive disorder. METHODS: A total of 106 HIV-infected outpatients with variable clinical characteristics were recruited in a multicenter investigation. NCI was diagnosed using a standardized neuropsychological tests battery (7 areas, 21 measures, ∼2 hours). Multiple score combinations were compared to find a paper-based method that took ≤10 minutes to apply. The presence of NCI was considered the gold standard for comparisons, and the sensitivity and specificity were calculated. RESULTS: Subjects were mostly middle-aged (median, 44 years) men (87%) on antiretroviral treatment. NCI was detected in 51 individuals (48%) and was associated with lower nadir CD4 count (P < 0.001), receiving antiretroviral therapy (P = 0.004), fewer years of education (P = 0.009), and presence of comorbidities (P < 0.001). The score combination that showed the highest sensitivity (74.5%) and specificity (81.8%) detecting NCI included 3 measures of attention/working memory, executive functioning, and verbal fluency (part A of Trail Making Test, part B of Trail Making Test, and Controlled Oral Word Association Test scores). A broader paper-based selection of measures covering 7 areas indicated a sensitivity of 100% and a specificity of 96.3% (7 measures, ∼35 minutes). CONCLUSIONS: The combination of the 3 measures presented in this study seems to be a rapid and feasible screening mean for NCI in HIV-infected patients. This approach, combined with screening for potential comorbidities and daily functioning interference, could help in the initial stages of a HIV-associated neurocognitive disorder diagnosis and in settings with limited access to neuropsychological resources.

Virological efficacy in cerebrospinal fluid and neurocognitive status in patients with long-term monotherapy based on lopinavir/ritonavir: an exploratory study.

BACKGROUND: Data on suppression of HIV replication in the CNS and on the subsequent risk of neurocognitive impairment using monotherapy with boosted protease inhibitors are limited. METHODS: Ours was an exploratory cross-sectional study in patients on lopinavir/ritonavir-based monotherapy (LPV/r-MT) or standard triple therapy (LPV/r-ART) for at least 96 weeks who maintained a plasma viral load <50 copies/mL. HIV-1 RNA in CSF was determined by HIV-1 SuperLow assay (lower limit of detection, 1 copy/mL). Neurocognitive functioning was assessed using a recommended battery of neuropsychological tests covering 7 areas. Neurocognitive impairment (NCI) was determined and also a global deficit score (GDS) for study comparisons. RESULTS: Seventeen patients on LPV/r-MT and 17 on LPV/r-ART were included. Fourteen (82.4%) patients on LPV/r-MT and 16 (94.1%) on LPV/r-ART had HIV-1 RNA <1 copy/mL in CSF (p = 0.601). NCI was observed in 7 patients on LPV/r-MT and in 10 on LPV/r-ART (41% vs 59%; p = 0.494). Mean (SD) GDS was 0.22 (0.20) in patients on LPV/r-MT and 0.47 (0.34) in those on LPV/r-ART (p = 0.012). CONCLUSIONS: Suppression of HIV in CSF is similar in individuals with durable plasma HIV-1 RNA suppression who are receiving LPV/r-MT or LPV/r-ART for at least 96 weeks. Findings for HIV-1 replication in CSF and neurocognitive status indicate that this strategy seems to be safe for CNS functioning.

Psychological stress is associated with high levels of IL-6 in HIV-1 infected individuals on effective combined antiretroviral treatment.

This study explores the role of psychological stress in the circulating levels of interleukin-6 (IL-6) in a group of HIV-1 infected individuals on effective cART. We developed a cross-sectional study with 50 individuals with confirmed diagnosis of HIV-1 infection ≥1 and ≤8 years, on continuous cART for >1 and <8 years and with plasma viral load <50 copies/mL for at least 1 year. Clinical, behavioral and psychological variables were collected to control their possible indirect contribution in the relationship between psychological stress and IL-6. Pearson correlation and univariate/multivariate logistic regressions were performed. Eighty-eight percent of the subjects were male: median (IQR) age: 39.0 (32.7-42.2), years since HIV-1 infection: 3.4 (2.1-7.0), years on cART: 2.5 (1.6-5.7), CD4 cell count: 709.0 (573.5-881.0) cell/mm(3), plasma levels of IL-6: 7.0 (0-12.2) pg/ml. A strong correlation between IL-6 and psychological stress was found (r=.81). Psychological stress (coef: 0.49; SD: 0.05), anxiety/depression (0.37; 0.08) and unhealthy diet (2.94; 1.38) were associated with higher levels of IL-6. In the multivariate model psychological stress remained strongly associated with IL-6 (R(2): 59%). In conclusion, individuals with psychological stress presented high levels of IL-6 and psychological stress was the only variable which remained strongly associated with IL-6. This strong relationship suggests evidence for a mechanism through which psychological stress might contribute to the health's impairment of HIV-infected individuals on effective cART.