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

2018 ◽  
Vol 6 (1) ◽  
pp. e512 ◽  
Author(s):  
Magnus Gisslén ◽  
Amanda Heslegrave ◽  
Elena Veleva ◽  
Aylin Yilmaz ◽  
Lars-Magnus Andersson ◽  
...  
Keyword(s):  
T Cell ◽  
Microglial Activation ◽  
Neuronal Injury ◽  
Cell Loss ◽  
Cross Sectional ◽  
Neurofilament Light ◽  
Cell Counts ◽  
Negative Controls ◽  
Hiv 1 ◽  
Hiv Negative

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

scholarly journals Occurrence of Accelerated Epigenetic Aging and Methylation Disruptions in Human Immunodeficiency Virus Infection Before Antiretroviral Therapy

2020 ◽  
Author(s):  
Chen Xi Yang ◽  
Emma Schon ◽  
Ma’en Obeidat ◽  
Michael S Kobor ◽  
Lisa McEwen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Cellular Aging ◽  
Epigenetic Clock ◽  
Cell Counts ◽  
Immunodeficiency Virus ◽  
Negative Controls ◽  
Hiv Negative

Abstract Background Whether accelerated aging develops over the course of chronic human immunodeficiency virus (HIV) infection or can be observed before significant immunosuppression on is unknown. We studied DNA methylation in blood to estimate cellular aging in persons living with HIV (PLWH) before the initiation of antiretroviral therapy (ART). Methods A total of 378 ART-naive PLWH who had CD4 T-cell counts >500/µL and were enrolled in the Strategic Timing of Antiretroviral Therapy trial (Pulmonary Substudy) were compared with 34 HIV-negative controls. DNA methylation was performed using the Illumina MethylationEPIC BeadChip. Differentially methylated positions (DMPs) and differentially methylated regions (DMRs) in PLWH compared with controls were identified using a robust linear model. Methylation age was calculated using a previously described epigenetic clock. Results There were a total of 56 639 DMPs and 6103 DMRs at a false discovery rate of <0.1. The top 5 DMPs corresponded to genes NLRC5, VRK2, B2M, and GPR6 and were highly enriched for cancer-related pathways. PLWH had significantly higher methylation age than HIV-negative controls (P = .001), with black race, low CD4 and high CD8 T-cell counts, and duration of HIV being risk factors for age acceleration. Conclusions PLWH before the initiation of ART and with preserved immune status show evidence of advanced methylation aging.

scholarly journals SARS-CoV-2 Evolution and Spike-Specific CD4+ T-Cell Response in Persistent COVID-19 with Severe HIV Immune Suppression

2022 ◽  
Vol 10 (1) ◽  
pp. 143
Author(s):  
Hortensia Álvarez ◽  
Ezequiel Ruiz-Mateos ◽  
Pedro Miguel Juiz-González ◽  
Joana Vitallé ◽  
Irene Viéitez ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Pneumocystis Jirovecii Pneumonia ◽  
Polymerase Chain ◽  
Host Evolution ◽  
Negative Controls ◽  
Hiv 1 ◽  
Hiv Negative

Intra-host evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been reported in cases with persistent coronavirus disease 2019 (COVID-19). In this study, we describe a severely immunosuppressed individual with HIV-1/SARS-CoV-2 coinfection with a long-term course of SARS-CoV-2 infection. A 28-year-old man was diagnosed with HIV-1 infection (CD4+ count: 3 cells/µL nd 563000 HIV-1 RNA copies/mL) and simultaneous Pneumocystis jirovecii pneumonia, disseminated Mycobacterium avium complex infection and SARS-CoV-2 infection. SARS-CoV-2 real-time reverse transcription polymerase chain reaction positivity from nasopharyngeal samples was prolonged for 15 weeks. SARS-CoV-2 was identified as variant Alpha (PANGO lineage B.1.1.7) with mutation S:E484K. Spike-specific T-cell response was similar to HIV-negative controls although enriched in IL-2, and showed disproportionately increased immunological exhaustion marker levels. Despite persistent SARS-CoV-2 infection, adaptive intra-host SARS-CoV-2 evolution, was not identified. Spike-specific T-cell response protected against a severe COVID-19 outcome and the increased immunological exhaustion marker levels might have favoured SARS-CoV-2 persistence.

scholarly journals Increased Platelet-CD4+ T Cell Aggregates Are Correlated With HIV-1 Permissiveness and CD4+ T Cell Loss

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiao-Peng Dai ◽  
Feng-Ying Wu ◽  
Cheng Cui ◽  
Xue-Jiao Liao ◽  
Yan-Mei Jiao ◽  
...  
Keyword(s):  
T Cell ◽  
Antiretroviral Therapy ◽  
Critical Role ◽  
Cell Loss ◽  
Cd4 T Cell ◽  
Cell Aggregates ◽  
Cell Aggregate ◽  
Aggregate Formation ◽  
Cell Counts ◽  
Hiv 1

Chronic HIV-1 infection is associated with persistent inflammation, which contributes to disease progression. Platelet-T cell aggregates play a critical role in maintaining inflammation. However, the phenotypic characteristics and clinical significance of platelet-CD4+ T cell aggregates remain unclear in different HIV-infected populations. In this study, we quantified and characterized platelet-CD4+ T cell aggregates in the peripheral blood of treatment-naïve HIV-1-infected individuals (TNs), immunological responders to antiretroviral therapy (IRs), immunological non-responders to antiretroviral therapy (INRs), and healthy controls (HCs). Flow cytometry analysis and immunofluorescence microscopy showed increased platelet-CD4+ T cell aggregate formation in TNs compared to HCs during HIV-1 infection. However, the frequencies of platelet-CD4+ T cell aggregates decreased in IRs compared to TNs, but not in INRs, which have shown severe immunological dysfunction. Platelet-CD4+ T cell aggregate frequencies were positively correlated with HIV-1 viral load but negatively correlated with CD4+ T cell counts and CD4/CD8 ratios. Furthermore, we observed a higher expression of CD45RO, HIV co-receptors, HIV activation/exhaustion markers in platelet-CD4+ T cell aggregates, which was associated with HIV-1 permissiveness. High levels of caspase-1 and caspase-3, and low levels of Bcl-2 in platelet-CD4+ T cell aggregates imply the potential role in CD4+ T cell loss during HIV-1 infection. Furthermore, platelet-CD4+ T cell aggregates contained more HIV-1 gag viral protein and HIV-1 DNA than their platelet-free CD4+ T cell counterparts. The platelet-CD4+ T cell aggregate levels were positively correlated with plasma sCD163 and sCD14 levels. Our findings demonstrate that platelet-CD4+ T cell aggregate formation has typical characteristics of HIV-1 permissiveness and is related to immune activation during HIV-1 infection.

scholarly journals Lymphocyte subset analysis to evaluate the prognosis of HIV-negative patients with pneumocystis pneumonia

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Fan Jin ◽  
Jing Xie ◽  
Huan-ling Wang
Keyword(s):  
T Cell ◽  
Cell Count ◽  
Lymphocyte Subsets ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Pneumocystis Pneumonia ◽  
Lymphocyte Subset ◽  
Cd4 T Cell ◽  
Cell Counts ◽  
Hiv Negative

Abstract Objectives We analysed the peripheral blood lymphocyte subsets of human immunodeficiency virus (HIV)-negative patients infected with pneumocystis pneumonia (PCP) to determine the relationships between the levels of different types of lymphocytes and the prognosis of patients. Methods We retrospectively reviewed HIV-negative patients with PCP diagnosed in our department. All the eligible patients underwent lymphocyte subset analysis on admission. Results A total of 88 HIV-negative PCP patients were enrolled in the study. In univariate analyses, low CD4+ T cell count, low CD8+ T cell count, and low natural killer cell (NK cell) count were associated with higher in-hospital mortality. CD8+ T cell count ≤300/μL was found to be an independent risk factor for poor prognosis in multivariate logistical regression analysis (p = 0.015, OR = 11.526, 95% CI = 1.597–83.158). Although low CD4+ T cell and NK cell counts were not independent risk factors, the mortality rates of PCP patients decreased as the CD4+ T cell and NK cell counts increased. Conclusion The immune process of Pneumocystis jirovecii infection is complex but important. We propose that lymphocyte subsets could give clinicians a better understanding of patient immune status, helping with the early identification of potentially lethal infections and treatment decision making, such as adjusting the immunosuppressive regimen and choosing an appropriate patient monitoring level.

scholarly journals Combination of Immune and Viral Factors Distinguishes Low-Risk versus High-Risk HIV-1 Disease Progression in HLA-B*5701 Subjects

2012 ◽  
Vol 86 (18) ◽  
pp. 9802-9816 ◽  
Author(s):  
Melissa M. Norström ◽  
Marcus Buggert ◽  
Johanna Tauriainen ◽  
Wendy Hartogensis ◽  
Mattia C. Prosperi ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
High Resolution ◽  
Disease Progression ◽  
T Cell Responses ◽  
Low Risk ◽  
Early Infection ◽  
Cell Responses ◽  
Cell Counts ◽  
Hiv 1

HLA-B*5701 is the host factor most strongly associated with slow HIV-1 disease progression, although rates can vary within this group. Underlying mechanisms are not fully understood but likely involve both immunological and virological dynamics. The present study investigated HIV-1in vivoevolution and epitope-specific CD8+T cell responses in six HLA-B*5701 patients who had not received antiretroviral treatment, monitored from early infection for up to 7 years. The subjects were classified as high-risk progressors (HRPs) or low-risk progressors (LRPs) based on baseline CD4+T cell counts. Dynamics of HIV-1 Gag p24 evolution and multifunctional CD8+T cell responses were evaluated by high-resolution phylogenetic analysis and polychromatic flow cytometry, respectively. In all subjects, substitutions occurred more frequently in flanking regions than in HLA-B*5701-restricted epitopes. In LRPs, p24 sequence diversity was significantly lower; sequences exhibited a higher degree of homoplasy and more constrained mutational patterns than HRPs. The HIV-1 intrahost evolutionary rate was also lower in LRPs and followed a strict molecular clock, suggesting neutral genetic drift rather than positive selection. Additionally, polyfunctional CD8+T cell responses, particularly to TW10 and QW9 epitopes, were more robust in LRPs, who also showed significantly higher interleukin-2 (IL-2) production in early infection. Overall, the findings indicate that HLA-B*5701 patients with higher CD4 counts at baseline have a lower risk of HIV-1 disease progression because of the interplay between specific HLA-linked immune responses and the rate and mode of viral evolution. The study highlights the power of a multidisciplinary approach, integrating high-resolution evolutionary and immunological data, to understand mechanisms underlying HIV-1 pathogenesis.

scholarly journals Dynamics and Correlates of CD8 T-Cell Counts in Africans with Primary Human Immunodeficiency Virus Type 1 Infection

2016 ◽  
Vol 90 (22) ◽  
pp. 10423-10430 ◽  
Author(s):  
Heather A. Prentice ◽  
Hailin Lu ◽  
Matthew A. Price ◽  
Anatoli Kamali ◽  
Etienne Karita ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
Human Leukocyte ◽  
Neutralizing Antibody ◽  
Sensitivity Analyses ◽  
Supporting Evidence ◽  
Cell Counts ◽  
Cellular And Humoral Immunity ◽  
Hiv 1

ABSTRACT In individuals with HIV-1 infection, depletion of CD4 + T cells is often accompanied by a malfunction of CD8 + T cells that are persistently activated and/or exhausted. While the dynamics and correlates of CD4 counts have been well documented, the same does not apply to CD8 counts. Here, we examined the CD8 counts in a cohort of 497 Africans with primary HIV-1 infection evaluated in monthly to quarterly follow-up visits for up to 3 years in the absence of antiretroviral therapy. Statistical models revealed that (i) CD8 counts were relatively steady in the 3- to 36-month period of infection and similar between men and women; (ii) neither geography nor heterogeneity in the HIV-1 set-point viral load could account for the roughly 10-fold range of CD8 counts in the cohort ( P > 0.25 in all tests); and (iii) factors independently associated with relatively high CD8 counts included demographics (age ≤ 40 years, adjusted P = 0.010) and several human leukocyte antigen class I (HLA-I) alleles, including HLA-A*03:01 ( P = 0.013), B*15:10 ( P = 0.007), and B*58:02 ( P < 0.001). Multiple sensitivity analyses provided supporting evidence for these novel relationships. Overall, these findings suggest that factors associated with the CD8 count have little overlap with those previously reported for other HIV-1-related outcome measures, including viral load, CD4 count, and CD4/CD8 ratio. IMPORTANCE Longitudinal data from 497 HIV-1 seroconverters allowed us to systematically evaluate the dynamics and correlates of CD8 + T-cell counts during untreated primary HIV-1 infection in eastern and southern Africans. Our findings suggest that individuals with certain HLA-I alleles, including A*03 (exclusively A*03:01), persistently maintain relatively high CD8 counts following HIV-1 infection, a finding which may offer an intriguing explanation for the recently reported, negative association of A*03 with HIV-1-specific, broadly neutralizing antibody responses. In future studies, attention to HLA-I genotyping data may benefit in-depth understanding of both cellular and humoral immunity, as well as the intrinsic balances of these types of immunity, especially in settings where there is emerging evidence of antagonism between the two arms of adaptive immunity.

scholarly journals Molecular transmission networks and pre-treatment drug resistance among individuals with acute HIV-1 infection in Baoding, China

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0260670
Author(s):  
Penghui Shi ◽  
Zhixia Chen ◽  
Juan Meng ◽  
Miaomiao Su ◽  
Xuegang Yang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Dynamic Networks ◽  
Cross Sectional Study ◽  
Gene Sequences ◽  
Cross Sectional ◽  
Transmission Networks ◽  
Cell Counts ◽  
Acute Hiv ◽  
Pre Treatment ◽  
Hiv 1

Background Human immunodeficiency virus type 1 (HIV-1) genetic diversity and pre-treatment drug resistance (PDR) are major barriers to successful antiretroviral therapy (ART). In China, sexual intercourse is the most frequent route of HIV-1 transmission. However, few studies have analyzed PDR and transmission networks in detail among individuals in China with acute HIV-1 infection and their sexual contacts. Methods A cross-sectional study was conducted in Baoding City, Hebei Province, China from 2019–2020. CD4 T cell counts and viral loads were assessed and a HIV-1 genotypic PDR assay was developed in-house. Transmission networks were visualized using Cytoscape with a threshold genetic distance of 0.015 among HIV-1 subtypes. Results From 139 newly diagnosed and drug-naïve individuals with HIV-1, 132 pol gene sequences were obtained and revealed eight HIV-1 subtypes. Circulating recombinant form (CRF)01_AE was the most frequent subtype (53.0%, 70/132) followed by CRF07_BC (26.5%, 35/132), B (13.6%, 18/132), unique recombinant forms (2.3%, 3/132), CRF55_01B (1.5%, 2/132), CRF103_01B (1.5%, 2/132), CRF65_cpx (0.8%, 1/132), and C (0.8%, 1/132). A total of 47 pol gene sequences were used to generate 10 molecular transmission networks. The overall prevalence of PDR was 7.6% and that of PDR to non-nucleotide reverse transcriptase inhibitors was 6.1%. Of three transmission networks for PDR, two were closely associated with Beijing and Tianjin, while another was restricted to sequences determined in this study. Conclusions These results demonstrate that during acute HIV-1 infection, PDR is transmitted in dynamic networks. This suggests that early detection, diagnosis, surveillance, and treatment are critical to effectively control HIV-1 spread.

scholarly journals Safety, pharmacokinetics and antiviral activity of PGT121, a broadly neutralizing monoclonal antibody against HIV-1: a randomized, placebo-controlled, phase 1 clinical trial

2021 ◽  
Author(s):  
Kathryn E. Stephenson ◽  
Boris Julg ◽  
C. Sabrina Tan ◽  
Rebecca Zash ◽  
Stephen R. Walsh ◽  
...  
Keyword(s):  
Viral Load ◽  
T Cell ◽  
Adverse Events ◽  
Antiviral Activity ◽  
Controlled Trial ◽  
Phase 1 ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Cell Counts ◽  
Hiv 1

AbstractHuman immunodeficiency virus (HIV)-1-specific broadly neutralizing monoclonal antibodies are currently under development to treat and prevent HIV-1 infection. We performed a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial of a single administration of the HIV-1 V3-glycan-specific antibody PGT121 at 3, 10 and 30 mg kg–1 in HIV-uninfected adults and HIV-infected adults on antiretroviral therapy (ART), as well as a multicenter, open-label trial of one infusion of PGT121 at 30 mg kg–1 in viremic HIV-infected adults not on ART (no. NCT02960581). The primary endpoints were safety and tolerability, pharmacokinetics (PK) and antiviral activity in viremic HIV-infected adults not on ART. The secondary endpoints were changes in anti-PGT121 antibody titers and CD4+ T-cell count, and development of HIV-1 sequence variations associated with PGT121 resistance. Among 48 participants enrolled, no treatment-related serious adverse events, potential immune-mediated diseases or Grade 3 or higher adverse events were reported. The most common reactions among PGT121 recipients were intravenous/injection site tenderness, pain and headache. Absolute and relative CD4+ T-cell counts did not change following PGT121 infusion in HIV-infected participants. Neutralizing anti-drug antibodies were not elicited. PGT121 reduced plasma HIV RNA levels by a median of 1.77 log in viremic participants, with a viral load nadir at a median of 8.5 days. Two individuals with low baseline viral loads experienced ART-free viral suppression for ≥168 days following antibody infusion, and rebound viruses in these individuals demonstrated full or partial PGT121 sensitivity. The trial met the prespecified endpoints. These data suggest that further investigation of the potential of antibody-based therapeutic strategies for long-term suppression of HIV is warranted, including in individuals off ART and with low viral load.

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