CD4+ T cell gene expression in virologically suppressed HIV-infected patients during Maraviroc intensification therapy.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE56804 | GEO | 2014/04/16
SECONDARY ACCESSION(S): PRJNA244635
REPOSITORIES: GEO
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Project description:Analysis of CD4+ T cell gene expression changes after 4 and 24 weeks of Maraviroc administration relative to baseline in 25 immunodiscordant patients with viral suppression. Maraviroc elicited very modest changes in CD4+ T cell transcriptome. The goal of this study was to identify genes with a potential role in Maraviroc-induced CD4+ T cell recovery in immunodiscordant patients. The study measured gene expression in CD4+ T cells isolated from the whole blood of HIV-infected patients before and at two time points after addition of Maraviroc to the baseline antiretroviral therapy. Thirty two patients were recruited from 3 sites, University of California, San Diego (UCSD), University of California, Los Angeles (UCLA) and University of Southern California (USC), and peripheral blood samples were obtained at 3 visits, week 0 (baseline), week 4 and week 24 after initiation of Maraviroc therapy. Because of poor RNA quality and outliers on the microarrays, 7 patients were excluded from the study. Non-outlier week 0 and week 24 arrays from one of the patients (Patient ID 01-005) were used for array data normalization and processing, but were not included in the time course analysis since the week 4 sample was not available.
2014-04-16 | E-GEOD-56804 | biostudies-arrayexpress
Project description:HIV-1-infected patients with suppressed plasma viral loads often require changes to their antiretroviral (ARV) therapy to manage drug toxicity and intolerance, to improve adherence, and to avoid drug interactions. In patients who have never experienced virologic failure while receiving ARV therapy and who have no evidence of drug resistance, switching to any of the acceptable US Department of Health and Human Services first-line therapies is expected to maintain virologic suppression. However, in virologically suppressed patients with a history of virologic failure or drug resistance, it can be more challenging to change therapy while still maintaining virologic suppression. In these patients, it may be difficult to know whether the discontinuation of one of the ARVs in a suppressive regimen constitutes the removal of a key regimen component that will not be adequately supplanted by one or more substituted ARVs. In this article, we review many of the clinical scenarios requiring ARV therapy modification in patients with stable virologic suppression and outline the strategies for modifying therapy while maintaining long-term virologic suppression.
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Project description:Comparison of total RNA-seq data from ex vivo unstimulated and stimulated (with anti-CD3/CD28) cells from two primary cell models of HIV latency (resting-cell and wild-type virus models) and peripheral CD4+ T cells from HIV-infected ART-suppressed individuals (ex vivo cells). Two donors were analyzed per model.
2020-10-28 | GSE144585 | GEO
Project description:ObjectiveGlycosylation plays a critical role in mediating several antibody (mainly immunoglobulin G; IgG) immunological functions, including antibody-dependent cell-mediated cytotoxicity (ADCC), and anti-inflammatory activities. We investigated whether IgG glycosylation and immune profile patterns are differentially modulated in mono and dual infection using samples from untreated hepatitis C virus (HCV)-infected individuals with and without co-infection with antiretroviral therapy (ART)-suppressed HIV.DesignIgG glycosylation, immune subsets, natural killer cell function, and liver enzymes were assessed in 14 HCV mono-infected and 27 ART-suppressed HIV/HCV co-infected participants naïve to HCV treatment. Historic IgG glycosylation data from 23 ART-suppressed chronically HIV-infected individuals were also used for comparisons.MethodsPlasma IgG glycosylation was assessed using capillary electrophoresis. Whole blood was used for immune subset characterization by flow cytometry. Peripheral blood mononuclear cells were used to measure constitutive and interferon-α-induced K562 target cell lysis. Statistical analysis was performed using R (3.5.0).ResultsHIV/HCV had lower levels of pro-ADCC-associated nonfucosylated glycans when compared with HIV [e.g. di-sialylated A2 percentage (%): P = 0.04], and higher levels of T and myeloid cell activation/exhaustion when compared with HCV (e.g. CD3CD8CD38 %: P < 0.001). Finally, in HCV high levels of the anti-inflammatory galactosylated and sialylated glycans were associated with low plasma levels of aspartate aminotransferase (AST), low CD8 T-cell activation, and high CD8 T-cell exhaustion.ConclusionHCV modulates IgG glycosylation profile in HIV co-infected individuals on suppressive ART. These results could inform on the modulation of IgG glycans in other mono and dual infections.
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Project description:Adoptive T cell therapy has had dramatic successes in the treatment of virus-related malignancies and infections following hematopoietic stem cell transplantation. We adapted this method to produce ex vivo expanded HIV-specific T cells (HXTCs), with the long-term goal of using HXTCs as part of strategies to clear persistent HIV infection. In this phase 1 proof-of-concept study (NCT02208167), we administered HXTCs to antiretroviral therapy (ART)-suppressed, HIV-infected participants. Participants received two infusions of 2 × 107 cells/m2 HXTCs at a 2-week interval. Leukapheresis was performed at baseline and 12 weeks post-infusion to measure the frequency of resting cell infection by the quantitative viral outgrowth assay (QVOA). Overall, participants tolerated HXTCs, with only grade 1 adverse events (AEs) related to HXTCs. Two of six participants exhibited a detectable increase in CD8 T cell-mediated antiviral activity following the two infusions in some, but not all, assays. As expected, however, in the absence of a latency reversing agent, no meaningful decline in the frequency of resting CD4 T cell infection was detected. HXTC therapy in ART-suppressed, HIV-infected individuals appears safe and well tolerated, without any clinical signs of immune activation, likely due to the low residual HIV antigen burden present during ART.
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Project description:We conducted a prospective study in 28 HIV/HCV-coinfected patients receiving IFN-based therapy at baseline (HIV/HCV-b) and week 24 after the sustained virological response (HIV/HCV-f). Twenty-seven HIV-monoinfected patients (HIV-group) were included as a control group, which were effectively treated with cART (virological controlled and CD4+ T-cell counts over 500) for an extended period. RNA-seq analysis was performed on peripheral blood mononuclear cells (PBMCs).
2021-05-05 | E-MTAB-10232 | biostudies-arrayexpress
Project description:Host directed therapies against HIV-1 are thought to be critical for long term containment of the HIV-1 pandemic but remain elusive. Since HIV-1 infects and manipulates important effectors of both the innate and adaptive immune system, identifying modulations of the host cell systems in humans during HIV-1 infection may be crucial for the development of immune based therapies. Here, we quantified the changes of the proteome in human CD4+ T cells upon HIV-1 infection, both in vitro and in vivo. A SWATH-MS approach was used to measure the proteome of human primary CD4+ T cells infected with HIV-1 in vitro as well as CD4+ T cells from HIV-1 infected patients with paired samples on and off antiretroviral treatment. In the in vitro experiment, the proteome of CD4+ T cells was quantified over a time course following HIV-1 infection. 1,725 host cell proteins and 4 HIV-1 proteins were quantified, with 145 proteins changing significantly during the time course. Changes in the proteome peaked 24 hours after infection, concomitantly with significant HIV-1 protein production. In the in vivo branch of the study, CD4+ T cells from viremic patients and those with no detectable viral load after treatment were sorted and the proteomes quantified. We consistently detected 895 proteins, 172 of which were considered to be significantly different between viraemic patients and patients undergoing successful treatment. The proteome of in vitro infected CD4+ T cells was modulated on multiple functional levels, including TLR-4 signalling and the type 1 interferon signalling pathway. Perturbations in the type 1 interferon signalling pathway were recapitulated in CD4+ T cells from patients. The study shows that proteome maps generated by SWATH-MS indicate a range of functionally significant changes in the proteome of HIV infected human CD4+ T cells. Exploring these perturbations in more detail may help identify new targets for immune based interventions.
2017-02-28 | PXD005234 | Pride
Project description:Broadly HIV-1 neutralizing VRC01-class antibodies target the CD4-binding site of Env. They are derived from VH1-2*02 antibody heavy chains paired with rare light chains expressing five amino acid long CDRL3s. They have been isolated from infected subjects but have not yet been elicited by immunization. Env-derived immunogens capable of binding the germline forms of VRC01 B cell receptors on naïve B cells have been designed and evaluated in knock-in mice. However, the elicited antibodies cannot bypass glycans present on the conserved position N276 of Env, which restricts access to the CD4-binding site. Efforts to guide the appropriate maturation of these antibodies by sequential immunization have not yet been successful. Here, we report on a two-step immunization scheme that led to the maturation of VRC01-like antibodies capable of accommodating the N276 glycan and displaying autologous tier 2 neutralizing activities. Our results are relevant to clinical trials aiming to elicit VRC01 antibodies.
2020-05-26 | PXD015168 | Pride
Project description:Persistence of human immunodeficiency virus (HIV) in a latent state in long-lived CD4+ T-cells is a major barrier to eradication. Latency-reversing agents that induce direct or immune-mediated cell death upon reactivation of HIV are a possible solution. However, clearance of reactivated cells may require immunotherapeutic agents that are fine-tuned to detect viral antigens when expressed at low levels. We tested the antiviral efficacy of immune-mobilizing monoclonal T-cell receptors against viruses (ImmTAVs), bispecific molecules that redirect CD8+ T-cells to kill HIV-infected CD4+ T-cells. T-cell receptors specific for an immunodominant Gag epitope, SL9, and its escape variants were engineered to achieve supraphysiological affinity and fused to a humanised CD3-specific single chain antibody fragment. Ex vivo polyclonal CD8+ T-cells were efficiently redirected by immune-mobilising monoclonal T-cell receptors against viruses to eliminate CD4+ T-cells from human histocompatibility leukocyte antigen (HLA)-A*0201-positive antiretroviral therapy-treated patients after reactivation of inducible HIV in vitro. The efficiency of infected cell elimination correlated with HIV Gag expression. Immune-mobilising monoclonal T-cell receptors against viruses have potential as a therapy to facilitate clearance of reactivated HIV reservoir cells.
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2020-05-15 | GSE126230 | GEO