RESUMO
Whereas human immunodeficiency virus (HIV) persists in tissue macrophages during antiretroviral therapy (ART), the role of circulating monocytes as HIV reservoirs remains controversial. Three magnetic bead selection methods and flow cytometry cell sorting were compared for their capacity to yield pure CD14+ monocyte populations. Cell sorting by flow cytometry provided the purest population of monocytes (median CD4+ T-cell contamination, 0.06%), and the levels of CD4+ T-cell contamination were positively correlated with the levels of integrated HIV DNA in the monocyte populations. Using cell sorting by flow cytometry, we assessed longitudinally the infection of monocytes and other cell subsets in a cohort of 29 Thai HIV-infected individuals. Low levels of HIV DNA were detected in a minority of monocyte fractions obtained before and after 1 year of ART (27% and 33%, respectively), whereas HIV DNA was readily detected in CD4+ T cells from all samples. Additional samples (2 to 5 years of ART) were obtained from 5 individuals in whom monocyte infection was previously detected. Whereas CD4+ T cells were infected at high levels at all time points, monocyte infection was inconsistent and absent in at least one longitudinal sample from 4/5 individuals. Our results indicate that infection of monocytes is infrequent and highlight the importance of using flow cytometry cell sorting to minimize contamination by CD4+ T cells.IMPORTANCE The role of circulating monocytes as persistent HIV reservoirs during ART is still controversial. Several studies have reported persistent infection of monocytes in virally suppressed individuals; however, others failed to detect HIV in this subset. These discrepancies are likely explained by the diversity of the methods used to isolate monocytes and to detect HIV infection. In this study, we show that only flow cytometry cell sorting yields a highly pure population of monocytes largely devoid of CD4 contaminants. Using this approach in a longitudinal cohort of HIV-infected individuals before and during ART, we demonstrate that HIV is rarely found in monocytes from untreated and treated HIV-infected individuals. This study highlights the importance of using methods that yield highly pure populations of cells as flow cytometry cell sorting to minimize and control for CD4+ T-cell contamination.
Assuntos
Fármacos Anti-HIV/uso terapêutico , DNA Viral/antagonistas & inibidores , Infecções por HIV/tratamento farmacológico , Monócitos/efeitos dos fármacos , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/classificação , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Estudos de Coortes , DNA Viral/genética , Citometria de Fluxo , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/patologia , HIV-1/efeitos dos fármacos , HIV-1/genética , HIV-1/crescimento & desenvolvimento , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Monócitos/classificação , Monócitos/imunologia , Monócitos/virologia , Cultura Primária de Células , Tailândia , Carga Viral/efeitos dos fármacosRESUMO
BACKGROUND: Chronic immune activation in the blood and central nervous system is a consequence of human immunodeficiency virus (HIV) infection that contributes to disease morbidity and can occur despite virally suppressive antiretroviral therapy (ART). The trajectory of HIV-related inflammation may vary with the timing of ART initiation. We examined immune activation markers in cerebrospinal fluid (CSF) and blood specimens collected over 96 weeks from participants who initiated ART during acute HIV infection (AHI). METHODS: RV254/SEARCH010 study participants with AHI underwent CSF (n = 89) and plasma (n = 146) sampling before initiating ART and at weeks 24 and 96 of treatment. A majority participants (64.4%) received a standard ART regimen (hereafter, "standard ART"), with some (34.7%) also receiving maraviroc and raltegravir for the first 24 weeks (hereafter, "ART plus"). We compared neopterin, CXCL10, CCL2, and interleukin 6 (IL-6) levels in the AHI group to those in 18 healthy, uninfected controls. RESULTS: Following 24 and 96 weeks of treatment, levels of all CSF markers normalized while levels of several plasma markers remained elevated in the AHI group (P < .001). Participants receiving the ART-plus regimen had lower median plasma CCL2 levels at week 24 and lower plasma neopterin levels at week 96. CONCLUSIONS: ART initiation during AHI differentially impacts the brain compartment, with markers of inflammation returning to normal levels in the CSF, where they were sustained at week 96, but not in plasma.
Assuntos
Biomarcadores , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/imunologia , Interações Hospedeiro-Patógeno/imunologia , Doença Aguda , Adulto , Antirretrovirais/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Contagem de Linfócito CD4 , Relação CD4-CD8 , Estudos de Coortes , Feminino , Infecções por HIV/metabolismo , Humanos , Ativação Linfocitária , Masculino , RNA Viral , Tempo para o Tratamento , Carga Viral , Adulto JovemRESUMO
Background: Many individuals with acute human immunodeficiency virus infection (AHI) experience acute retroviral syndrome (ARS), which is associated with adverse long-term clinical outcomes. Methods: Participants presenting for voluntary human immunodeficiency virus (HIV) testing were enrolled during AHI in Bangkok, Thailand. ARS was defined by ≥3 qualifying signs/symptoms. HIV burden, immunophenotypes, and biomarkers were stratified by ARS diagnosis at enrollment and after up to 96 weeks of antiretroviral therapy (ART). Results: From 212382 samples screened, 430 participants were enrolled during AHI, including 335 (78%) with ARS. Median age was 26 years and 416 (97%) were men. Sixty (14%) underwent sigmoid biopsy and 105 (24%) underwent lumbar puncture during AHI. Common symptoms included fever (93%), fatigue (79%), pharyngitis (67%), and headache (64%). Compared to those without ARS, participants with ARS were in later Fiebig stages with higher HIV RNA in blood, colon, and cerebrospinal fluid; higher total HIV DNA in blood; CD4 depletion in blood and colon; and elevated plasma tumor necrosis factor alpha (TNF-α), C-reactive protein, and D-dimer (all P < .05). Subgroup analyses of Fiebig I/II participants (95 with ARS, 69 without) demonstrated similar findings. After 96 weeks of ART, TNF-α and interleukin 6 were elevated in the ARS group (P < .05) but other biomarkers equilibrated. Conclusions: ARS was associated with high viral burden, CD4 depletion, and immune activation across multiple body compartments during AHI and prior to ART. Persistent inflammation despite suppressive ART could contribute to increased morbidity in individuals who experience ARS.
Assuntos
Síndrome Retroviral Aguda/patologia , Síndrome Retroviral Aguda/virologia , Contagem de Linfócito CD4 , Fenômenos do Sistema Imunitário/fisiologia , Imunidade Celular/fisiologia , Carga Viral , Síndrome Retroviral Aguda/epidemiologia , Síndrome Retroviral Aguda/imunologia , Adulto , Antirretrovirais/uso terapêutico , Biomarcadores , Doenças do Sistema Nervoso Central/etiologia , Doenças do Sistema Nervoso Central/patologia , Doenças do Sistema Nervoso Central/virologia , DNA Viral/isolamento & purificação , Feminino , Gastroenteropatias/imunologia , Gastroenteropatias/patologia , Gastroenteropatias/virologia , HIV-1 , Humanos , Inflamação/metabolismo , Inflamação/patologia , Masculino , RNA Viral , Tailândia/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Serious non-AIDS events cause substantial disease and death despite human immunodeficiency virus (HIV) suppression with antiretroviral therapy (ART). Biomarkers of inflammation, coagulation cascade activation, and fibrosis predict these end-organ events. We aimed to determine whether ART initiation during acute HIV infection would attenuate changes in these biomarker levels. METHODS: Plasma samples were obtained from participants starting ART during acute or chronic HIV infection and from HIV-uninfected participants from Bangkok, Thailand. Biomarkers of inflammation (C-reactive protein [CRP], interleukin 6, soluble interleukin 6 receptor [sIL-6R], soluble gp130, tumor necrosis factor [TNF]), enterocyte turnover (intestinal fatty acid binding protein [I-FABP]), lipopolysaccharide-induced monocyte activation (soluble CD14 [sCD14]), coagulation cascade activation [D-dimer], and fibrosis (hyaluronic acid [HA]) were measured at baseline and through 96 weeks of ART. RESULTS: CRP, TNF, sIL-6R, I-FABP, sCD14, D-dimer, and HA levels were elevated in acute HIV infection. Early ART was associated with increased I-FABP levels but normalization of TNF, sIL-6R, and D-dimer levels. CRP, sCD14, and HA levels decreased during ART but remained elevated compared with HIV-uninfected participants. Higher sCD14, CRP, and D-dimer levels were associated with higher peripheral blood mononuclear cell and gut integrated HIV DNA levels. Decreases in sCD14 and CRP levels were correlated with increases in CD4 T-cell counts. CONCLUSIONS: ART initiated in early acute HIV infection was associated with normalization of the coagulation cascade and several systemic inflammatory biomarkers, but the acute-phase response, enterocyte turnover, monocyte activation, and fibrosis biomarkers remained elevated. Additional interventions to attenuate inflammation may be needed to optimize clinical outcomes in persons with HIV infection.
Assuntos
Infecções por HIV/complicações , Infecções por HIV/virologia , Inflamação/complicações , Inflamação/metabolismo , Adulto , Terapia Antirretroviral de Alta Atividade , Biomarcadores , Coagulação Sanguínea , Contagem de Linfócito CD4 , Feminino , Fibrose , Microbioma Gastrointestinal , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Inflamação/patologia , Mediadores da Inflamação , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Masculino , Permeabilidade , Carga Viral , Adulto JovemRESUMO
BACKGROUND: Third- and fourth-generation immunoassays (IAs) are widely used in the diagnosis of human immunodeficiency virus (HIV) infection. Antiretroviral therapy (ART) during acute HIV infection (AHI) may impact HIV-specific antibodies, with failure to develop antibody or seroreversion. We report on the ability of diagnostic tests to detect HIV-specific antibodies in Thai participants initiating ART during AHI. METHODS: Participants with detectable plasma HIV RNA but nonreactive HIV-specific immunoglobulin G, enrolled in an AHI study, were offered immediate initiation of ART. Participants were tested at initiation and at 12 and 24 weeks following treatment using standard second-, third-, and fourth-generation IAs and Western blot (WB). RESULTS: Participants (N = 234) initiating ART at a median of 19 days (range, 1-62 days) from HIV exposure demonstrated different frequencies of reactivity prior to and following 24 weeks of ART depending on the IA. Third-generation IA nonreactivity prior to ART was 48%, which decreased to 4% following ART (P < .001). Fourth-generation IA nonreactivity was 18% prior to ART and 17% following ART (P = .720). Negative WB results were observed in 89% and 12% of participants prior to and following 24 weeks of ART, respectively (P < .001). Seroreversion to nonreactivity during ART was observed to at least one of the tests in 20% of participants, with fourth-generation IA demonstrating the highest frequency (11%) of seroreversion. CONCLUSIONS: HIV-specific antibodies may fail to develop and, when detected, may decline when ART is initiated during AHI. Although fourth-generation IA was the most sensitive at detecting AHI prior to ART, third-generation IA was the most sensitive during treatment. CLINICAL TRIALS REGISTRATION: NCT00796146 and NCT00796263.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Anticorpos Anti-HIV/sangue , Infecções por HIV/imunologia , HIV-1/imunologia , Imunoglobulina G/sangue , Doença Aguda , Adolescente , Adulto , Estudos de Coortes , Testes Diagnósticos de Rotina , Feminino , Infecções por HIV/tratamento farmacológico , Soropositividade para HIV , HIV-1/genética , Homossexualidade Masculina , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Viral/sangue , Minorias Sexuais e de Gênero , Tailândia , Adulto JovemRESUMO
BACKGROUND: It is unknown whether neuronal injury begins during acute human immunodeficiency virus (HIV) infection, and whether immediate initiation of combination antiretroviral therapy (cART) prevents neuronal injury. METHODS: Cerebrospinal fluid (CSF) neurofilament light chain (NFL), a measure of axonal injury, was assessed before and after cART initiation in individuals starting treatment during acute or chronic HIV infection. Nonparametric statistics examined relationships between NFL and disease progression, neuroinflammation, and cognitive performance. RESULTS: Before treatment, subjects with acute infection had lower CSF NFL levels, with elevations for their age in 1 of 32 subjects with acute infection (3.1%) and 10 of 32 with chronic infection (31%) (P = .006). This persisted after cART initiation, with 1 of 25 acute (4%) and 4 of 9 chronic subjects (44%) showing elevated NFL levels (P = .01). In acute infection, pre-cART NFL levels were inversely correlated with proton magnetic resonance spectroscopic findings of N-acetylaspartate/creatine in frontal gray matter (r = -0.40; P = .03), frontal white matter (r = -0.46; P = .01), and parietal gray matter (r = -0.47; P = .01); correlations persisted after treatment in the frontal white matter (r = -0.51; P = .02) and parietal gray matter (r = -0.46; P = .04). CONCLUSIONS: CSF NFL levels are not elevated in untreated acute HIV infection or after 6 months of immediately initiated cART but are abnormal in chronic HIV infection before and after treatment. In acute HIV infection, CSF NFL levels are inversely associated with neuroimaging markers of neuronal health.
Assuntos
Antirretrovirais , Infecções por HIV/líquido cefalorraquidiano , Infecções por HIV/tratamento farmacológico , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Adulto , Antirretrovirais/administração & dosagem , Antirretrovirais/uso terapêutico , Estudos de Coortes , Feminino , Infecções por HIV/epidemiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Neuroimagem , Adulto JovemRESUMO
This study aimed to determine the effects of human immunodeficiency virus (HIV) on brain structure in HIV-infected individuals with and without HIV-associated neurocognitive disorders (HAND). Twenty-nine HIV-uninfected controls, 37 HIV+, treatment-naïve, individuals with HAND (HIV+HAND+; 16 asymptomatic neurocognitive impairment (ANI), 12 mild neurocognitive disorder (MND), and 9 HIV-associated dementia HAD), and 37 HIV+, treatment-naïve, individuals with normal cognitive function (HIV+HAND-) underwent magnetic resonance imaging (MRI) and neuropsychological assessment. The HIV-infected participants had a mean (SD) age of 35 (7) years, mean (interquartile range (IQR)) CD4 count of 221 (83-324), and mean (IQR) log10 plasma viral load of 4.81 (4.39-5.48). Six regions of interest were selected for analyses including total and subcortical gray matter, total white matter, caudate, corpus callosum, and thalamus. The HIV+/HAND+ group exhibited significantly smaller brain volumes compared to the HIV-uninfected group in subcortical gray and total gray matter; however, there were no statistically significant differences in brain volumes between the HIV+HAND+ and HIV+HAND- groups or between HIV+/HAND- and controls. CD4 count at time of combination antiretroviral therapy (cART) initiation was associated with total and subcortical gray matter volumes but not with cognitive measures. Plasma viral load correlated with neuropsychological performance but not brain volumes. The lack of significant differences in brain volumes between HIV+HAND+ and HIV+HAND- suggests that brain atrophy is not a sensitive measure of HAND in subjects without advanced immunosuppression. Alternatively, current HAND diagnostic criteria may not sufficiently distinguish patients based on MRI measures of brain volumes.
Assuntos
Complexo AIDS Demência/patologia , Encéfalo/patologia , Adulto , Atrofia/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Tamanho do Órgão , TailândiaRESUMO
OBJECTIVE: A longitudinal cohort study was conducted in Bangkok, Thailand between 2008 and 2013 in order to determine the practice effect of serial neuropsychological testing and establish normative data among normal (HIV-uninfected) Thai volunteers. MATERIAL AND METHOD: The authors enrolled 511 cognitively healthy individuals (HIV-uninfected, no drug abuse or other previous/current neurological or psychological conditions) to assess baseline performance on a HIV-specific neuropsychological testing battery. Ninety-nine subjects were re-assessed at 6 and 12 months to evaluate practice effects. RESULTS: The mean age of the 99 subjects completing longitudinal visits was 49.2 years and 53 were male. The authors identified improved mean raw scores on most neuropsychological tests with repeated measurements; however only change in WHO Auditory Verbal Learning Test (AVLT) scores (learning, attention, immediate and delayed recall tasks) met statistical significance, with larger differences seen between baseline and 6-month compared to 6 and 12 months follow-up. Older age correlated with poorer baseline raw score, and was a predictor of worse performance at 6 months and 12 months on several tasks. Level of education was associated with practice effects on several tests. No similar effects were observed with gender. CONCLUSION: The authors identified improved performance after repeated measurements revealing a significant practice effect on an HIV-specific neuropsychological testing battery employed in Bangkok, Thailand. Main predictors were age and educational attainment.
Assuntos
Infecções por HIV/psicologia , Testes Neuropsicológicos , Adulto , Idoso , Povo Asiático , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Desempenho Psicomotor , Valores de Referência , TailândiaRESUMO
BACKGROUND: Fourth generation (4thG) immunoassay (IA) is becoming the standard HIV screening method but was not available when the Fiebig acute HIV infection (AHI) staging system was proposed. Here we evaluated AHI staging based on a 4thG IA (4thG staging). FINDINGS: Screening for AHI was performed in real-time by pooled nucleic acid testing (NAT, n=48,828 samples) and sequential enzyme immunoassay (EIA, n=3,939 samples) identifying 63 subjects with non-reactive 2nd generation EIA (Fiebig stages I (n=25), II (n=7), III (n=29), IV (n=2)). The majority of samples tested (n=53) were subtype CRF_01AE (77%). NAT+ subjects were re-staged into three 4thG stages: stage 1 (n=20; 4th gen EIA-, 3rd gen EIA-), stage 2 (n=12; 4th gen EIA+, 3rd gen EIA-), stage 3 (n=31; 4th gen EIA+, 3rd gen EIA+, Western blot-/indeterminate). 4thG staging distinguishes groups of AHI subjects by time since presumed HIV exposure, pattern of CD8+ T, B and natural killer cell absolute numbers, and HIV RNA and DNA levels. This staging system further stratified Fiebig I subjects: 18 subjects in 4thG stage 1 had lower HIV RNA and DNA levels than 7 subjects in 4thG stage 2. CONCLUSIONS: Using 4th generation IA as part of AHI staging distinguishes groups of patients by time since exposure to HIV, lymphocyte numbers and HIV viral burden. It identifies two groups of Fiebig stage I subjects who display different levels of HIV RNA and DNA, which may have implication for HIV cure. 4th generation IA should be incorporated into AHI staging systems.
Assuntos
Infecções por HIV/diagnóstico , Infecções por HIV/patologia , Programas de Rastreamento/métodos , Índice de Gravidade de Doença , Adulto , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , DNA Viral/sangue , Feminino , Infecções por HIV/imunologia , Humanos , Imunoensaio/métodos , Células Matadoras Naturais/imunologia , Masculino , RNA Viral/sangue , Fatores de Tempo , Carga ViralRESUMO
Although HIV-associated dementia (HAD) occurs in less than 5 % of individuals with access to combination antiretroviral therapy, rates of milder forms of HIV-associated neurocognitive disorder (HAND) are much higher. We sought to define an optimal cut point for the International HIV Dementia Scale (IHDS) in Thailand for the identification of symptomatic HAND, defined as both HAD and mild neurocognitive disorder. We then sought to determine if adding a simple test from a larger neuropsychological battery could improve the performance characteristics for identifying symptomatic HAND. In this study, subjects comprising 75 seropositive adults in Bangkok, Thailand, completed neuropsychological tests and underwent a full neurological assessment. HAND diagnoses were determined by consensus conference using the 2007 Frascati criteria, blinded to the IHDS results. The optimal IHDS cut point was determined by receiver operating characteristic analysis with cross-validation. Individual neuropsychological tests were then evaluated and combined with the IHDS to test performance characteristics. The IHDS was poor at detecting symptomatic HAND at the optimized cut point of ≤ 10 (sensitivity, 53.3 %; specificity, 89.8 %). Trail Making Test A was most effective in improving performance characteristics when combined with the IHDS, with net sensitivity of 86 % and specificity of 79 %. In this setting, the IHDS performed poorly in identifying symptomatic HAND, but was substantially improved by the addition of Trail Making Test A, which typically requires less than 2 min to complete. This combination should be validated in a larger setting since it may address the critical need for HAND screening instruments in international settings.
Assuntos
Complexo AIDS Demência/psicologia , Disfunção Cognitiva/psicologia , Projetos de Pesquisa/estatística & dados numéricos , Teste de Sequência Alfanumérica/estatística & dados numéricos , Complexo AIDS Demência/diagnóstico , Complexo AIDS Demência/virologia , Adulto , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/virologia , Feminino , Humanos , Masculino , Curva ROC , Índice de Gravidade de Doença , TailândiaRESUMO
Human immunodeficiency virus (HIV) is a rapidly evolving virus, allowing its genetic sequence to act as a fingerprint for epidemiological processes among, as well as within, individual infected hosts. Though primarily infecting the CD4+ T-cell population, HIV can also be found in monocytes, an immune cell population that differs in several aspects from the canonical T-cell viral target. Using single genome viral sequencing and statistical phylogenetic inference, we investigated the viral RNA diversity and relative contribution of each of these immune cell types to the viral population within the peripheral blood. Results provide evidence of an increased prevalence of circulating monocytes harboring virus in individuals with high viral load in the absence of suppressive antiretroviral therapy. Bayesian phyloanatomic analysis of three of these individuals demonstrated a measurable role for these cells, but not the circulating T-cell population, as a source of cell-free virus in the plasma, supporting the hypothesis that these cells can act as an additional conduit of virus spread.
RESUMO
OBJECTIVE AND DESIGN: A randomized, open-label pilot study in individuals treated with antiretroviral therapy (ART) since acute HIV infection (AHI) with a regimen including a histone deacetylase inhibitor to induce HIV from latency and control HIV replication during subsequent treatment interruption (TI). METHODS: Fifteen participants who initiated ART at AHI were randomized to vorinostat/hydroxychloroquine/maraviroc (VHM) plus ART (n â= â10) or ART alone (n â= â5). The VHM arm received three 14-day vorinostat cycles within 10 weeks before TI. ART was resumed for plasma viral load (VL) â> â1,000 HIV RNA copies/mL. Primary outcome was proportion of participants on VHM â+ âART versus ART only with VL â< â50 copies/mL for 24 weeks after TI. RESULTS: Fifteen participants on ART (median: 178 weeks: range 79-295) enrolled. Two on VHM â+ âART experienced serious adverse events. Fourteen participants underwent TI; all experienced VL rebound with no difference in time between arms: VHM â+ âART (n â= â9) median: 4 weeks and ART only (n â= â5) median: 5 weeks. VHM induced a 2.2-fold increase in VL (p â= â0.008) by single-copy HIV RNA assay after the first cycle. Neopterin levels increased significantly following the first two cycles. After VHM treatment, the frequencies of peripheral blood mononuclear cells harboring total HIV DNA and cell-associated RNA were unchanged. All participants achieved VL suppression following ART re-initiation. CONCLUSIONS: Administration of VHM increased HIV VL in plasma, but this was not sustained. VHM did not impact time to viral rebound following TI and had no impact on the size of the HIV reservoir, suggesting that HIV reservoir elimination will require alternative treatment strategies.
RESUMO
A history of implants used for orthodontic anchorage is given. Sizes and head designs of implants and guidelines for their placement are listed. Clinical cases are shown so that practitioners can visualize how implants can be used to improve their orthodontics.
Assuntos
Parafusos Ósseos , Implantes Dentários , Procedimentos de Ancoragem Ortodôntica/instrumentação , Ortodontia Corretiva/métodos , Técnicas de Movimentação Dentária/instrumentação , Humanos , Miniaturização , Procedimentos de Ancoragem Ortodôntica/métodos , Ortodontia Corretiva/instrumentação , Técnicas de Movimentação Dentária/métodosRESUMO
Background: HIV RNA is identified in cerebrospinal fluid (CSF) within eight days of estimated viral exposure. Neurological findings and impaired neuropsychological testing performance are documented in a subset of individuals with acute HIV infection (AHI). The purpose of this study was to determine whether microstructural white matter and resting-state functional connectivity (rsFC) are disrupted in AHI. Methods: We examined 49 AHI (100% male; mean ageâ¯=â¯30⯱â¯SD 9.9) and 23 HIV-uninfected Thai participants (78% male; ageâ¯=â¯30⯱â¯5.5) with diffusion tensor imaging (DTI) and rsFC acquired at 3 Tesla, and four neuropsychological tests (summarized as NPZ-4). MRI for the AHI group was performed prior to combination antiretroviral treatment (ART) in 26 participants and on average two days (range:1-5) after ART in 23 participants. Fractional anisotropy (FA), mean (MD), axial (AD), and radial diffusivity (RD) were quantified for DTI. Seed-based voxelwise rsFC analyses were completed for the default mode (DMN), fronto-parietal, and salience and 6 subcortical networks. rsFC and DTI analyses were corrected for family-wise error, with voxelwise comparisons completed using t-tests. Group-specific voxelwise regressions were conducted to examine relationships between imaging indices, HIV disease variables, and treatment status. Results: The AHI group had a mean (SD) CD4 count of 421(234)â¯cells/mm3 plasma HIV RNA of 6.07(1.1)â¯log10â¯copies/mL and estimated duration of infection of 20(5.5) days. Differences between AHI and CO groups did not meet statistical significance for DTI metrics. Within the AHI group, voxelwise analyses revealed associations between brief exposure to ART and higher FA and lower RD and MD bilaterally in the corpus callosum, corona radiata, and superior longitudinal fasciculus (pâ¯<â¯0.05). Diffusion indices were unrelated to clinical variables or NPZ-4. The AHI group had reduced rsFC between left parahippocampal cortex (PHC) of the DMN and left middle frontal gyrus compared to CO (pâ¯<â¯0.002). Within AHI, ART status was unrelated to rsFC. However, higher CD4 cell count associated with increased rsFC for the right lateral parietal and PHC seeds in the DMN. Direct associations were noted between NPZ-4 correspond to higher rsFC of the bilateral caudate seed (pâ¯<â¯0.002). Conclusions: Study findings reveal minimal disruption to structural and functional brain integrity in the earliest stages of HIV. Longitudinal studies are needed to determine if treatment with ART initiated in AHI is sufficient to prevent the evolution of brain dysfunction identified in chronically infected individuals.
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Infecções por HIV/diagnóstico por imagem , Infecções por HIV/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Doença Aguda , Adulto , Imagem de Tensor de Difusão/métodos , Feminino , Humanos , MasculinoRESUMO
HIV-associated neurocognitive disorder (HAND) remains a challenge despite antiretroviral therapy (ART), and has been linked to monocyte/macrophage (M/M) migration to the brain. Due to the potential impact of T cell effector mechanisms in eliminating activated/HIV-infected M/M, T cell activation may play a role in the development of HAND. We sought to investigate the relationship between cognition and both CD8+ T cell activation (HLA-DR+/CD38+) and HIV-specific CD8+ T cell responses at the time of HIV diagnosis and 12 months postinitiation of ART. CD8+ T cell activation was increased in HAND compared to cognitive normal (NL) individuals and correlated directly with plasma viral load and inversely with the cognitive status. In addition, Gag-specific cytolytic activity (CD107a/b+) was decreased in HAND compared with NL individuals and correlated with their neurological testing, suggesting a potential role of cytotoxic CD8+ T cells in the mechanism of HAND development.
Assuntos
Complexo AIDS Demência/patologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/complicações , Infecções por HIV/imunologia , Imunidade Celular , Ativação Linfocitária , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Plasma/virologia , Tailândia , Carga Viral , Adulto JovemRESUMO
OBJECTIVE: To characterize cerebrospinal fluid (CSF) YKL-40, a unique biomarker that reflects activation of microglial cells, in acute (AHI) and chronic HIV-1 infection (CHI) and to determine the effect of treatment initiation on levels of this marker. DESIGN: A cross-sectional study of two groups of HIV-infected participants at baseline and follow-up timepoints. METHODS: AHI (nâ=â33) and CHI (nâ=â34) participants underwent CSF and blood sampling before treatment initiation with combination antiretroviral therapy (cART) and at follow-up on cART in a subset of these individuals [6 months in AHI participants (nâ=â24), 1 year in CHI participants (nâ=â10)]. Measured parameters were analyzed at each timepoint. Analyses employed Mann-Whitney tests and Spearman correlations. RESULTS: Baseline median YKL-40 was higher in CHI than AHI (96844 versus 80754âng/l; Pâ=â0.011). Elevations in the CHI group relative to the AHI group persisted at follow-up despite treatment (87414 versus 66130âng/l; Pâ=â0.003). In untreated CHI, YKL-40 correlated with neopterin (râ=â0.51, Pâ=â0.0025), chemokine (CXC-motif) ligand-10 (râ=â0.44, Pâ=â0.011), and neurofilament light chain (râ=â0.56, Pâ=â0.0008) in CSF. CONCLUSIONS: This study is the first to describe the dynamics of CSF YKL-40 in two groups of HIV-infected individuals before and after cART and demonstrates the value of this marker in understanding HIV neuropathogenesis. The results suggest the utility of further exploring the prognostic value of YKL-40, particularly in individuals with early HIV infection or those initiating treatment during CHI.
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Antirretrovirais/uso terapêutico , Líquido Cefalorraquidiano/química , Proteína 1 Semelhante à Quitinase-3/líquido cefalorraquidiano , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Transtornos Neurocognitivos/patologia , Prevenção Secundária , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Adulto JovemRESUMO
INTRODUCTION: Antiretroviral treatment (ART) reduces HIV transmission. Despite increased ART coverage, incidence remains high among men who have sex with men (MSM) in many places. Acute HIV infection (AHI) is characterized by high viral replication and increased infectiousness. We estimated the feasible reduction in transmission by targeting MSM with AHI for early ART. METHODS: We recruited a cohort of 88 MSM with AHI in Bangkok, Thailand, who initiated ART immediately. A risk calculator based on viral load and reported behaviour, calibrated to Thai epidemiological data, was applied to estimate the number of onwards transmissions. This was compared with the expected number without early interventions. RESULTS: Forty of the MSM were in 4th-generation AHI stages 1 and 2 (4thG stage 1, HIV nucleic acid testing (NAT)+/4thG immunoassay (IA)-/3rdG IA-; 4thG stage 2, NAT+/4thG IA+/3rdG IA-) while 48 tested positive on third-generation IA but had negative or indeterminate western blot (4thG stage 3). Mean plasma HIV RNA was 5.62 log10 copies/ml. Any condomless sex in the four months preceding the study was reported by 83.7%, but decreased to 21.2% by 24 weeks on ART. After ART, 48/88 (54.6%) attained HIV RNA <50 copies/ml by week 8, increasing to 78/87 (89.7%), and 64/66 (97%) at weeks 24 and 48, respectively. The estimated number of onwards transmissions in the first year of infection would have been 27.3 (95% credible interval: 21.7-35.3) with no intervention, 8.3 (6.4-11.2) with post-diagnosis behaviour change only, 5.9 (4.4-7.9) with viral load reduction only and 3.1 (2.4-4.3) with both. The latter was associated with an 88.7% (83.8-91.1%) reduction in transmission. CONCLUSIONS: Disproportionate HIV transmission occurs during AHI. Diagnosis of AHI with early ART initiation can substantially reduce onwards transmission.
Assuntos
Infecções por HIV/diagnóstico , Infecções por HIV/transmissão , Tempo para o Tratamento , Carga Viral , Doença Aguda , Adulto , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Homossexualidade Masculina , Humanos , Masculino , Estudos Prospectivos , Fatores de Risco , Comportamento Sexual , TailândiaRESUMO
CD8+ T cells play a critical role in controlling HIV viremia and could be important in reducing HIV-infected cells in approaches to eradicate HIV. The simian immunodeficiency virus model provided the proof of concept for a CD8+ T cell-mediated reservoir clearance but showed conflicting evidence on the role of these cells to eliminate HIV-infected cells. In humans, HIV-specific CD8+ T cell responses have not been associated with a reduction of the HIV-infected cell pool in vivo. We studied HIV-specific CD8+ T cells in the RV254 cohort of individuals initiating ART in the earliest stages of acute HIV infection (AHI). We showed that the HIV-specific CD8+ T cells generated as early as AHI stages 1 and 2 before peak viremia are delayed in expanding and acquiring effector functions but are endowed with higher memory potential. In contrast, the fully differentiated HIV-specific CD8+ T cells at peak viremia in AHI stage 3 were more prone to apoptosis but were associated with a steeper viral load decrease after ART initiation. Their capacity to persist in vivo after ART initiation correlated with a lower HIV DNA reservoir. These findings demonstrate that HIV-specific CD8+ T cell magnitude and differentiation are delayed in the earliest stages of infection. These results also demonstrate that potent HIV-specific CD8+ T cells contribute to the reduction of the pool of HIV-producing cells and the HIV reservoir seeding in vivo and provide the rationale to design interventions aiming at inducing these potent responses to cure HIV infection.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Reservatórios de Doenças/virologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Viremia/imunologia , Doença Aguda , Adulto , Terapia Antirretroviral de Alta Atividade , Proliferação de Células , Citocinas/metabolismo , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Humanos , Masculino , Análise de Sobrevida , Carga Viral , Viremia/virologiaRESUMO
BACKGROUND: Central nervous system (CNS) infiltration by CD8 T cells is associated with neuroinflammation in many neurodegenerative diseases, including HIV-associated dementia. However, the role of CD8 T cells in the CNS during acute HIV infection (AHI) is unknown. METHODS: We analyzed the phenotype, gene expression, T cell receptor (TCR) repertoire, and HIV specificity of CD8 T cells in cerebrospinal fluid (CSF) of a unique cohort captured during the earliest stages of AHI (n = 26), chronic (n = 23), and uninfected (n = 8). RESULTS: CSF CD8 T cells were elevated in AHI compared with uninfected controls. The frequency of activated CSF CD8 T cells positively correlated to CSF HIV RNA and to markers of CNS inflammation. In contrast, activated CSF CD8 T cells during chronic HIV infection were associated with markers of neurological injury and microglial activation. CSF CD8 T cells in AHI exhibited increased functional gene expression profiles associated with CD8 T cells effector function, proliferation, and TCR signaling, a unique restricted TCR Vbeta repertoire and contained HIV-specific CD8 T cells directed to unique HIV epitopes compared with the periphery. CONCLUSIONS: These results suggest that CSF CD8 T cells in AHI expanding in the CNS are functional and directed against HIV antigens. These cells could thus play a beneficial role protective of injury seen in chronic HIV infection if combination antiretroviral therapy is initiated early.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Líquido Cefalorraquidiano/citologia , Líquido Cefalorraquidiano/imunologia , Antígenos HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/patologia , Subpopulações de Linfócitos T/imunologia , Humanos , ImunofenotipagemRESUMO
OBJECTIVE: Combination antiretroviral therapy (cART) can suppress plasma HIV RNA to undetectable levels; yet reports indicate persistent HIV-associated neurocognitive disorders (HAND) among treated individuals. We sought to investigate imaging correlates of incomplete cognitive recovery among individuals with chronic HIV. METHODS: We used single voxel proton magnetic resonance spectroscopy in 4 regions of the brain to measure changes in neuronal and glia biomarkers in cART-naive subjects before (n = 59, 27 with HAND) and after 12 months of cART. RESULTS: At baseline, we observed elevated total choline (CHO) in the basal ganglia (BG, P = 0.002) and in the posterior cingulate gyrus (PCG, P = 0.022) associated with HIV infection. Myo-inositol (MI) was elevated in the frontal white matter (FWM, P = 0.040). N-acetylaspartate was elevated in the BG (P = 0.047). Using a mixed model approach among all HIV-infected individuals, at 6 months, we observed decreased n- acetylaspartate in FWM (P = 0.031), decreased creatine in PCG (P = 0.026) and increased MI in frontal gray matter (FGM, P = 0.023). At 12 months, we observed an increase in BG MI (P = 0.038) and in FGM (P = 0.021). Compared to those with normal cognition, HAND cases had higher FGM MI (P = 0.014) at baseline. At 12 months, individuals that remained cognitively impaired compared with those without HAND exhibited elevated CHO in the PCG (P = 0.018) and decreased glutamate in both FWM (P = 0.027) and BG (P = 0.013). CONCLUSIONS: cART started during chronic HIV is associated with reduced neuronal-glia and inflammatory markers. Alterations in CHO are noted among individuals who remain impaired after 12 months of cART.