Blood amyloid-ß protein isoforms are affected by HIV-1 in a subtype-dependent pattern.

This study aimed to compare serum amyloid processing biomarkers among HIV subtype B (n = 25), HIV subtype C (n = 26), healthy HIV-negative controls (n = 18), and patients with Alzheimer's disease (AD; n = 24). Immunoassays were used to measure main soluble Aß isoforms Aß38, Aß40, Aß42, and Aß-total in serum and cerebrospinal fluid (CSF). People living with HIV (PLWH) and HIV(-) samples, including AD samples, were compared for gender and age, while HIV subtypes were compared for nadir CD4 and plasma viral load suppression. CSF/serum ratios of Aß40, Aß42, and Aß-total were lower in HIV-1C group than in HIV-1B group (p = 0.020, 0.025, and 0.050, respectively). In serum, these biomarkers were comparable. Serum Aß isoforms were significantly lower in PLWH than in AD. Serum Aß42 levels in PLWH were decreased compared to those in control group, thus similar to Aß42 alterations in CSF; these results were different from those observed in AD. Impaired cellular immunity, low CD4 cell count (nadir or current) influences serum Aß metabolism in HIV-1B but not HIV-1C. However, in PLWH overall, but not in individual HIV subtype groups, greater CD4 recovery, calculated as the difference between current and nadir CD4, correlated with Aß42/Aß40 ratio in serum (rs 0.246; p = 0.0479). No significant correlation was found with global deficit score (GDS), an index of neurocognitive performance, age, or duration of infection. These findings are consistent with those of subtype-dependent amyloid processing in blood in chronic HIV disease.

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.

Biomarkers of neuronal injury and amyloid metabolism in the cerebrospinal fluid of patients infected with HIV-1 subtypes B and C.

Based on prior reports that the HIV-1 Tat protein modulates amyloid-beta (Aß) metabolism, this study aimed to compare CSF neural injury biomarkers between 27 patients with HIV subtype B, 26 patients with HIV subtype C, 18 healthy HIV-negative controls, and 24 patients with Alzheimer's disease (AD). Immunoassays were used to measure soluble amyloid precursor protein α and ß (sAPPα, sAPPß), Aß oligomers 38, 40, 42, and Aß-total; phosphorylated tau (P-tau181), and total tau (T-tau). Comparisons between HIV(+) and HIV(-) (including AD) were adjusted by linear regression for gender and age; HIV subtype comparisons were adjusted for nadir CD4 and plasma viral load suppression. The p values were corrected for multiple testing with the Benjamini-Hochberg procedure. CSF Aß-42 and Hulstaert (P-tau181) index were lower in HIV1-C than B (p = 0.03, and 0.049 respectively); subtypes did not differ on other CSF biomarkers or ratios. Compared to AD, HIV(+) had lower CSF levels of T-tau, P-tau181 (p < 0.001), and sAPPα (p = 0.041); HIV(+) had higher CSF Aß-42 (p = 0.002) and higher CSF indexes: [Aß-42/(240 + 1.18 T-tau)], P-tau181/Aß-42, T-tau/Aß-42, P-tau181/T-tau, sAPPα/ß (all p ≤ 0.01) than AD. Compared to HIV(-), HIV(+) had lower CSF Aß-42, and T-tau (all p ≤ 0.004). As conclusion, amyloid metabolism was influenced by HIV infection in a subtype-dependent manner. Aß-42 levels were lower in HIV1-C than B, suggesting that there may be greater deposition of Aß-42 in HIV1-C. These findings are supported by CSF Hulstaert (P-tau181) index. Differences between HIV and AD in the patterns of Aß and Tau biomarkers suggest that CNS HIV infection and AD may not share some of same mechanisms of neuronal injury.

Neurocognitive impairment with hepatitis C and HIV co-infection in Southern Brazil.

Although cognitive impairment has been well documented in human immunodeficiency virus (HIV) and hepatitis C virus (HCV) mono-infections, research on neurocognitive effects is limited in the context of HIV/HCV co-infection. The aims of this study were to explore the interplay between HIV and HCV infections in the expression of neurocognitive impairment (NCI), and to examine the differences in test performance between HIV/HCV co-infected and HIV or HCV mono-infected patients. A total of 128 participants from Southern Brazil underwent a comprehensive neuropsychological (NP) battery comprising 18 tests. Participants were grouped according to their serological status: HCV mono-infected (n = 20), HIV mono-infected (n = 48), HIV/HCV co-infected (n = 12), and HIV-/HCV-uninfected controls (n = 48). The frequencies of HIV subtypes B and C between the HIV mono-infected and HIV/HCV co-infected groups were comparable. There was greater prevalence of neuropsychological impairment among all three infection groups compared with the uninfected control group, but no statistically significant differences among mono- and co-infected groups were found. HCV infection was associated with cognitive deficits, independently of liver dysfunction. HCV infection did not show an additive effect on neurocognitive function among HIV+. NCI was independent of HCV RNA on peripheral blood, CSF, and hepatic injury. While we did not find additive global effect, in the present study, there was some evidence of additive HIV/HCV co-infection effects in speed of information processing, executive function, and verbal fluency domains when comparing the co-infected group with the other three groups. NP impairment was not dependent on HCV subtypes.

Dynamic of CSF and serum biomarkers in HIV-1 subtype C encephalitis with CNS genetic compartmentalization-case study.

Despite the effective suppression of viremia with antiretroviral therapy, HIV can still replicate in the central nervous system (CNS). This was a longitudinal study of the cerebrospinal fluid (CSF) and serum dynamics of several biomarkers related to inflammation, the blood-brain barrier, neuronal injury, and IgG intrathecal synthesis in serial samples of CSF and serum from a patient infected with HIV-1 subtype C with CNS compartmentalization.The phylogenetic analyses of plasma and CSF samples in an acute phase using next-generation sequencing and F-statistics analysis of C2-V3 haplotypes revealed distinct compartmentalized CSF viruses in paired CSF and peripheral blood mononuclear cell samples. The CSF biomarker analysis in this patient showed that symptomatic CSF escape is accompanied by CNS inflammation, high levels of cell and humoral immune biomarkers, CNS barrier dysfunction, and an increase in neuronal injury biomarkers with demyelization. Independent and isolated HIV replication can occur in the CNS, even in HIV-1 subtype C, leading to compartmentalization and development of quasispecies distinct from the peripheral plasma. These immunological aspects of the HIV CNS escape have not been described previously. To our knowledge, this is the first report of CNS HIV escape and compartmentalization in HIV-1 subtype C.

Biomarkers of chemotaxis and inflammation in cerebrospinal fluid and serum in individuals with HIV-1 subtype C versus B.

A defective chemokine motif in the HIV-1 Tat protein has been hypothesized to alter central nervous system cellular trafficking and inflammation, rendering HIV-1 subtype C less neuropathogenic than B. To evaluate this hypothesis, we compared biomarkers of cellular chemotaxis and inflammation in cerebrospinal fluid (CSF) and serum in individuals infected with HIV-1 subtypes B (n = 27) and C (n = 25) from Curitiba, Brazil. None had opportunistic infections. Chemokines (MCP-1, MIP-1α, MIP-1ß, RANTES, IP-10) and cytokines (TNF-α, IFN-γ, IL-1ß, IL-2, IL-4, IL-6, IL-7, IL-10) were measured using the multiplex bead suspension array immunoassays or ELISA HD. CSF and serum biomarker concentrations were compared between subtype B and C groups and HIV-positive and HIV-negative subjects (N = 19) using an independent group t test (unadjusted analysis) and linear regression (adjusted analysis), controlling for nadir CD4 and CSF and plasma HIV RNA suppression. CSF levels of cytokines and chemokines were significantly (p < 0.05) elevated in HIV-positive versus HIV-negative participants for 7/13 biomarkers measured, but levels did not differ for subtypes B and C. Serum levels were significantly elevated for 4/13 markers, with no significant differences between subtypes B and C. Although pleocytosis was much more frequent in HIV-positive than in HIV-negative individuals (27 vs. 0 %), subtypes B and C did not differ (32 and 22 %; p = 0.23). We did not find molecular evidence to support the hypothesis that intrathecal chemotaxis and inflammation is less in HIV-1 subtype C than in subtype B. Biomarker changes in CSF were more robust than in serum, suggesting compartmentalization of the immunological response to HIV.

Neurocytoskeleton Proteins in Cerebrospinal Fluid of People With HIV-1 Subtypes B and C.

BACKGROUND: The objective was to compare the effect of HIV-1C and HIV-1B subtypes on neurofilament light (NfL) cerebrospinal fluid (CSF) levels and ratios of NfL to tau proteins. Additional comparisons were performed between people with HIV (PWH), participants with Alzheimer disease (AD), and HIV-negative controls (HIV-). We also calculated the diagnostic characteristics of CSF NfL and its ratios in HIV-associated neurocognitive disorder (HAND) diagnosis. METHODS: CSF NfL, T-tau, and P-tau181 concentrations were measured using immunoassays in a total of 108 CSF samples, including PWH (n = 68), HIV- (n = 16), and participants with AD (n = 24). These proteins were compared between HIV-1B (n = 27) and HIV-1C (n = 26) using multiple linear regression adjusted for nadir CD4 and plasma viral load suppression. Comparisons between PWH, HIV-, and participants with AD were adjusted for gender and age. RESULTS: CSF neurocytoskeleton proteins and their ratios were comparable in HIV-1B and HIV-1C. However, the HIV-1C group had a higher proportion of samples of CSF NfL above the reference value (n = 14, 53.85%) than the HIV-1B group (n = 8, 29.63%), P = 0.098. The values of CSF NfL were higher in the AD group [2578 (1864; 3500) pg/mL] than those in PWH [683 (500; 1197) pg/mL, P < 0.001] and control [660 (539; 802) pg/mL, P = 0.012] groups. The value of CSF NfL and its ratios for HAND diagnosis were poor. CONCLUSION: The effects of HIV-1B and HIV-1C on CSF NfL and tau ratios were comparable. The differences in CSF neurocytoskeleton proteins between PWH and individuals with AD suggested they might not share the same mechanisms of impairment. Further research is necessary to evaluate CSF NfL on the differential diagnoses of HAND with AD.

Neprilysin in the Cerebrospinal Fluid and Serum of Patients Infected With HIV1-Subtypes C and B.

OBJECTIVE: Neprilysin (NEP) is the dominant Aß peptide-degrading enzyme in the brain. HIV-1 subtype B transactivator of transcription protein is known to interfere with NEP function, but whether this is true of HIV-1C transactivator of transcription, which has a defective chemokine motif, is not known. This study aimed to analyze the impact of HIV subtype on NEP-mediated cleavage of Aß by comparing cerebrospinal fluid (CSF) and serum levels of NEP between HIV+ (27 patients with HIV-1B and 26 with HIV-1C), healthy HIV- controls (n = 13), and patients with Alzheimer disease (n = 24). METHODS: NEP and Aß oligomers 38, 40, 42 levels were measured in CSF and serum by immunoassays. Ratios between NEP and Aß-38, 40, 42, and total were calculated in CSF and serum. Comparisons between HIV(+) and HIV(-) were adjusted by linear regression for sex and age; HIV subtype comparisons were adjusted for nadir CD4 and plasma viral load suppression. RESULTS: Levels of NEP and ratios in CSF were comparable for HIV-1C and B subtypes. The ratio of serum NEP/Aß-40 was lower for HIV1-C than HIV1-B (P = 0.032). The CSF/serum index of NEP/Aß-40, NEP/Aß-42, and NEP/Aß-total were lower for HIV1-B than HIV1-C (P = 0.008, 0.005, and 0.017, respectively), corroborating the findings for serum. CSF NEP was comparable for HIV+, HIV-, and AD. CONCLUSION: There was impact of HIV subtype on NEP. The ratio of NEP/Aß-40 on serum was lower on HIV1-C than HIV1-B. These results are consistent with the results of CSF Aß-42 levels decreased in HIV1-C compared with HIV1-B, suggesting higher amyloid ß deposit on HIV1-C than HIV1-B.

Impact of public health strategies on reducing AIDS mortality in southern Brazil.

In Brazil, all patients who fulfill the criteria for AIDS have had free access to antiretroviral therapy since 1996. We performed this cross-sectional study to evaluate the causes of death among 643 HIV-infected patients over three non-consecutive years (2000, 2006, and 2010), using their epidemiological, clinical, and laboratory data. The causes of death were classified as AIDS-defining or non-AIDS-defining conditions. We observed a progressive increase in the prevalence of HIV infection over the study period, although there was also a decrease in the mortality rate for various groups, and especially among pediatric patients. An AIDS-defining condition was recorded as the cause of death for approximately 30% of the patients. There was also a high frequency (>70%) of infectious and parasitic diseases, including opportunistic infections, and the most common diagnoses were septicemia, pneumonia, tuberculosis, and pneumocystosis. Acute respiratory failure was the underlying cause of death in 30% of these cases. Despite advances in HIV therapy, the mortality rate remains high in Brazil. As few Brazilian studies have investigated HIV/AIDS-related mortality, it is important to evaluate and improve the mortality notification databases, in order to provide information regarding the effects of HIV and to guide the implementation of appropriate healthcare measures.

Improving Detection of HIV-Associated Cognitive Impairment: Comparison of the International HIV Dementia Scale and a Brief Screening Battery.

OBJECTIVES: The International HIV Dementia Scale (IHDS) was developed to screen for HIV-associated dementia, but it has been used more generally for HIV-associated neurocognitive disorder (HAND). This study sought to examine the accuracy of the IHDS in a cohort of Brazilian HIV-infected individuals and compare its performance to an alternative screening battery for detecting HAND. METHODS: A total of 108 participants (including 60 HIV-infected persons) completed the IHDS and a gold standard neuropsychological (NP) battery of 17 tests. As alternative screening method, all possible 3-test combinations from the NP battery were examined and a superiority index (a marker of specificity and sensitivity) was calculated. RESULTS: Sensitivity and specificity to HAND using the standard IHDS cutpoint of 10 were 36% and 75%, respectively. The best balance between sensitivity and specificity was accomplished with a modified cutpoint of 11.5, which yielded sensitivity of 72% and specificity of 58%. The top two most sensitive test combinations, compared with the gold standard NP battery, were Trail Making Test A, Wechsler Adult Intelligence Scale III Digit Symbol and Hopkins Verbal Learning Test-Revised Total Recall (sensitivity 91%, specificity 96%), and Digit Symbol, Brief Visuospatial Memory Test-Revised Total Recall and Grooved Pegboard Test-dominant hand (sensitivity 94%, specificity 91%). CONCLUSIONS: Both test combinations can be administered in less than 10 minutes and were more accurate than the IHDS in classifying HIV+ participants as NP impaired or unimpaired. These data suggest that demographically corrected T-scores from commonly used NP measures with modest time and material demands can improve identification of patients with HAND who may benefit from a more extensive NP examination.

Blood-CSF barrier and compartmentalization of CNS cellular immune response in HIV infection.

HIV infection is persistent in the CNS, to evaluate the compartmentalization of the CNS immune response to HIV, we compared soluble markers of cellular immunity in the blood and CSF among HIV- (n=19) and HIV+ (n=68), as well as among HIV participants with or without CSF pleocytosis. Dysfunction of the blood cerebrospinal fluid barrier (BCSFB) was common in HIV participants. CSF levels of TNFα, IFNγ, IL-2, IL-6, IL-7, IL-10, IP-10, MIP-1α, MIP-1ß, and RANTES were significantly higher in participants with CSF pleocytosis (P<0.05); serum levels of these biomarkers were comparable. The CNS immune response is compartmentalized, and remains so despite the BCSFB dysfunction during HIV infection; it is markedly reduced by virology suppression, although BCSFB dysfunction persists on this subgroup.