Browse
Submit Data
Databases
API
Help

Dataset Information

20 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Increased homeostatic cytokines and stability of HIV-infected memory CD4 T-cells identify individuals with suboptimal CD4 T-cell recovery on-ART.

ABSTRACT: Clinical outcomes are inferior for individuals with HIV having suboptimal CD4 T-cell recovery during antiretroviral therapy (ART). We investigated if the levels of infection and the response to homeostatic cytokines of CD4 T-cell subsets contributed to divergent CD4 T-cell recovery and HIV reservoir during ART by studying virologically-suppressed immunologic responders (IR, achieving a CD4 cell count >500 cells/μL on or before two years after ART initiation), and virologically-suppressed suboptimal responders (ISR, did not achieve a CD4 cell count >500 cells/μL in the first two years after ART initiation). Compared to IR, ISR demonstrated higher levels of HIV-DNA in naïve, central (CM), transitional (TM), and effector (EM) memory CD4 T-cells in blood, both pre- and on-ART, and specifically in CM CD4 T-cells in LN on-ART. Furthermore, ISR had higher pre-ART plasma levels of IL-7 and IL-15, cytokines regulating T-cell homeostasis. Notably, pre-ART PD-1 and TIGIT expression levels were higher in blood CM and TM CD4 T-cells for ISR; this was associated with a significantly lower fold-changes in HIV-DNA levels between pre- and on-ART time points exclusively on CM and TM T-cell subsets, but not naïve or EM T-cells. Finally, the frequency of CM CD4 T-cells expressing PD-1 or TIGIT pre-ART as well as plasma levels of IL-7 and IL-15 predicted HIV-DNA content on-ART. Our results establish the association between infection, T-cell homeostasis, and expression of PD-1 and TIGIT in long-lived CD4 T-cell subsets prior to ART with CD4 T-cell recovery and HIV persistence on-ART.

SUBMITTER: Pino M

PROVIDER: S-EPMC8397407 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Enrichment of gut-derived Fusobacterium is associated with suboptimal immune recovery in HIV-infected individuals.

Project description:We explored the gut microbiota profile among HIV-infected individuals with diverse immune recovery profiles following long-term suppressive ART and investigated the relationship between the altered bacteria with markers of immune dysfunction. The microbiota profile of rectal swabs from 26 HIV-infected individuals and 20 HIV-uninfected controls were examined. Patients were classified as suboptimal responders, sIR (n?=?10, CD4 T-cell?<350 cells/ul) and optimal responders, oIR (n?=?16, CD4 T-cell?>500 cells/ul) after a minimum of 2 years on suppressive ART. Canonical correlation analysis(CCA) and multiple regression modelling were used to explore the association between fecal bacterial taxa abundance and immunological profiles in optimal and suboptimal responders. We found Fusobacterium was significantly enriched among the HIV-infected and the sIR group. CCA results showed that Fusobacterium abundance was negatively correlated with CD4 T-cell counts, but positively correlated with CD4 T-cell activation and CD4 Tregs. Multiple linear regression analysis adjusted for age, baseline CD4 T-cell count, antibiotic exposure and MSM status indicated that higher Fusobacterium relative abundance was independently associated with poorer CD4 T-cell recovery following ART. Enrichment of Fusobacterium was associated with reduced immune recovery and persistent immune dysfunction following ART. Modulating the abundance of this bacterial taxa in the gut may be a viable intervention to improve immune reconstitution in our setting.

| S-EPMC6155144 | biostudies-literature

HIV-Infected Individuals on ART With Impaired Immune Recovery Have Altered Plasma Metabolite Profiles.

Project description:BackgroundMultiple host factors may influence immune reconstitution in HIV-infected people after the initiation of suppressive antiretroviral therapy (ART). Aberrant metabolic pathways have been reported in people with HIV (PWH) on ART. We hypothesized that alterations in plasma metabolites were associated with immune recovery following ART.MethodsIn this cross-sectional study, the plasma metabolomic profiles of PWH on ART were evaluated. PWH of slow and fast immune recovery were classified by increase in CD4 T cells following 2 years of ART. Targeted plasma metabolite profiling by liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry to determine metabolite signatures for HIV recovery identified >200 metabolites.ResultsNotably, indole-3-propionic acid was downregulated during HIV, possibly reflecting impaired gastrointestinal epithelium homeostasis. The most important metabolite discriminating between the PWH with fast and slow immune recovery was cysteine. Upregulated cysteine and cysteine pathways may contribute to redox-balance maintenance and T-cell function in PWH with fast immune recovery. Additionally, serine and glycine metabolism and bile acid biosynthesis were the most perturbed metabolic pathways in PWH.ConclusionsThese results provide a starting point for developing biomarker candidates for immune recovery in PWH on ART and provide insight into the interplay of metabolism and immune response in HIV infection.

| S-EPMC8271132 | biostudies-literature

Gp120/CD4 blocking antibodies are frequently elicited in ART-naive chronically HIV-1 infected individuals.

Project description:Antibodies with the ability to block the interaction of HIV-1 envelope glycoprotein (Env) gp120 with CD4, including those overlapping the CD4 binding site (CD4bs antibodies), can protect from infection by HIV-1, and their elicitation may be an interesting goal for any vaccination strategy. To identify gp120/CD4 blocking antibodies in plasma samples from HIV-1 infected individuals we have developed a competitive flow cytometry-based functional assay. In a cohort of treatment-naïve chronically infected patients, we showed that gp120/CD4 blocking antibodies were frequently elicited (detected in 97% plasma samples) and correlated with binding to trimeric HIV-1 envelope glycoproteins. However, no correlation was observed between functional CD4 binding blockade data and titer of CD4bs antibodies determined by ELISA using resurfaced gp120 proteins. Consistently, plasma samples lacking CD4bs antibodies were able to block the interaction between gp120 and its receptor, indicating that antibodies recognizing other epitopes, such as PGT126 and PG16, can also play the same role. Antibodies blocking CD4 binding increased over time and correlated positively with the capacity of plasma samples to neutralize the laboratory-adapted NL4.3 and BaL virus isolates, suggesting their potential contribution to the neutralizing workforce of plasma in vivo. Determining whether this response can be boosted to achieve broadly neutralizing antibodies may provide valuable information for the design of new strategies aimed to improve the anti-HIV-1 humoral response and to develop a successful HIV-1 vaccine.

| S-EPMC4372395 | biostudies-literature

Altered responses to homeostatic cytokines in patients with idiopathic CD4 lymphocytopenia.

Project description:Idiopathic CD4 lymphocytopenia (ICL) is a rare immune deficiency characterized by a protracted CD4(+) T cell loss of unknown etiology and by the occurrence of opportunistic infections similar to those seen in AIDS. We investigated whether a defect in responses to cytokines that control CD4(+) T cell homeostasis could play a role in ICL. Immunophenotype and signaling responses to interleukin-7 (IL-7), IL-2, and thymic stromal lymphopoietin (TSLP) were analyzed by flow cytometry in CD4(+) T cells from 15 ICL patients and 15 healthy blood donors. The induction of phospho-STAT5 after IL-7 stimulation was decreased in memory CD4(+) T cells of some ICL patients, which correlated with a decreased expression of the IL-7R? receptor chain (R?=?0.74, p<0.005) and with lower CD4(+) T cell counts (R?=?0.69, p<0.005). IL-2 responses were also impaired, both in the Treg and conventional memory subsets. Decreased IL-2 responses correlated with decreased IL-7 responses (R?=?0.75, p<0.005), pointing to combined defects that may significantly perturb CD4(+) T cell homeostasis in a subset of ICL patients. Unexpectedly, responses to the IL-7-related cytokine TSLP were increased in ICL patients, while they remained barely detectable in healthy controls. TSLP responses correlated inversely with IL-7 responses (R?=?-0.41; p<0.05), suggesting a cross-regulation between the two cytokine systems. In conclusion, IL-7 and IL-2 signaling are impaired in ICL, which may account for the loss of CD4(+) T cell homeostasis. Increased TSLP responses point to a compensatory homeostatic mechanism that may mitigate defects in ?c cytokine responses.

| S-EPMC3559496 | biostudies-literature

Virologic and immunologic effects of adding maraviroc to suppressive antiretroviral therapy in individuals with suboptimal CD4+ T-cell recovery.

Project description:Combination antiretroviral therapy (ART) suppresses HIV-1 replication, but does not restore CD4 T-cell counts in all individuals. To investigate the effects of maraviroc on HIV-1 persistence and the relations between virologic and immunologic parameters in individuals with incomplete CD4 T-cell recovery, we performed a prospective, open-label pilot trial in which maraviroc was added to a suppressive ART regimen for 24 weeks.A5256 was a single-arm trial in which individuals on suppressive ART with incomplete CD4 T-cell recovery added maraviroc for 24 weeks.We quantified low-level, residual viremia in plasma and total HIV-1 DNA and 2-long terminal repeat (2-LTR) circles in peripheral blood mononuclear cells before and after maraviroc intensification. We also evaluated markers of CD4 and CD8 T-cell immune activation (%CD38HLA-DR) and apoptosis (%caspase3/Bcl-2).No effect of maraviroc was found on the probability of detectable plasma viremia (?1?copy/ml; n?=?31, exact McNemar P?=?1.0) or detectable 2-LTR circles (n?=?28, P?=?0.25) or on total HIV-1 DNA (n?=?28, 90% confidence interval -0.1, +0.3 log10?copies/10 CD4 T-cells). Premaraviroc HIV-1 DNA levels were inversely related to premaraviroc %CD38HLA-DR CD4 T-cells (Spearman?=?-0.52, P?=?0.004), and lower premaraviroc HIV-1 DNA levels were associated with larger decreases in %CD38HLA-DR CD4 T-cells during maraviroc intensification (Spearman?=?0.44, P?=?0.018).In individuals on suppressive ART with incomplete CD4 T-cell recovery, maraviroc intensification did not affect measures of HIV-1 persistence but did decrease persistent CD4 T-cell immune activation especially in individuals with low preintensification levels of HIV-1 DNA.

| S-EPMC4638139 | biostudies-literature

CD4+CD38+ central memory T cells contribute to HIV persistence in HIV-infected individuals on long-term ART.

Project description:BACKGROUND:Despite the effective antiretroviral treatment (ART) of HIV-infected individuals, HIV persists in a small pool. Central memory CD4+ T cells (Tcm) make a major contribution to HIV persistence. We found that unlike HLA-DR, CD38 is highly expressed on the Tcm of HIV-infected subjects receiving ART for?>?5 years. It has been reported that the half-life of total and episomal HIV DNA in the CD4+CD38+ T cell subset, exhibits lower decay rates at 12 weeks of ART. Whether CD38 contributes to HIV latency in HIV-infected individuals receiving long-term ART is yet to be addressed. METHODS:Peripheral blood mononuclear cells (PBMCs) were isolated from the whole blood of HIV-infected subjects receiving suppressive ART. The immunophenotyping, proliferation and apoptosis of CD4+ T cell subpopulations were detected by flow cytometry, and the level of CD38 mRNA and total HIV DNA were measured using real-time PCR and digital droplet PCR, respectively. A negative binomial regression model was used to determine the correlation between CD4+CD38+ Tcm and total HIV DNA in CD4+ T cells. RESULTS:CD38 was highly expressed on CD4+ Tcm cells from HIV infected individuals on long-term ART. Comparing with HLA-DR-Tcm and CD4+HLA-DR+ T cells, CD4+CD38+ Tcm cells displayed lower levels of activation (CD25 and CD69) and higher levels of CD127 expression. The proportion of CD38+ Tcm, but not CD38- Tcm cells can predict the total HIV DNA in the CD4+ T cells and the CD38+ Tcm subset harbored higher total HIV DNA copy numbers than the CD38- Tcm subset. After transfected with CD38 si-RNA in CD4+ T cells, the proliferation of CD4+ T cells was inhibited. CONCLUSION:The current date indicates that CD4+CD38+ Tcm cells contribute to HIV persistence in HIV-infected individuals on long-term ART. Our study provides a potential target to resolve HIV persistence.

| S-EPMC7038621 | biostudies-literature

Gene expression before HAART initiation predicts HIV-infected individuals at risk of poor CD4+ T-cell recovery.

Project description:To identify a pre-HAART gene expression signature in peripheral blood mononuclear cells (PBMCs) predictive of CD4 T-cell recovery during HAART in HIV-infected individuals.This retrospective study evaluated PBMC gene expression in 24 recently HIV-infected individuals before the initiation of HAART to identify genes whose expression is predictive of CD4 T-cell recovery after 48 weeks of HAART.The change in CD4 T-cell count (DeltaCD4) over the 48-week study period was calculated for each of the 24 participants. Twelve participants were assigned to the 'good' (DeltaCD4 > or = 200 cells/microl) and 12 to the 'poor' (DeltaCD4 < 200 cells/microl) CD4 T-cell recovery group. Gene expression profiling of the entire transcriptome using Illumina BeadChips was performed with PBMC samples obtained before HAART. Gene expression classifiers capable of predicting CD4 T-cell recovery group (good vs. poor), as well as the specific DeltaCD4 value, at week 48 were constructed using methods of Class Prediction.The expression of 40 genes in PBMC samples taken before HAART predicted CD4 T-cell recovery group (good vs. poor) at week 48 with 100% accuracy. The expression of 22 genes predicted a specific DeltaCD4 value for each HIV-infected individual that correlated well with actual values (R = 0.82). Predicted DeltaCD4 values were also used to assign individuals to good vs. poor CD4 T-cell recovery groups with 79% accuracy.Gene expression in PBMCs can be used as biomarkers to successfully predict disease outcomes among HIV-infected individuals treated with HAART.

| S-EPMC2915828 | biostudies-other

Elevated humoral response to cytomegalovirus in HIV-infected individuals with poor CD4+ T-cell immune recovery.

Project description:Some HIV-infected c-ART-suppressed individuals show incomplete CD4+ T-cell recovery, abnormal T-cell activation and higher mortality. One potential source of immune activation could be coinfection with cytomegalovirus (CMV). IgG and IgM levels, immune activation, inflammation and T-cell death in c-ART-suppressed individuals with CD4+ T-cell counts >350 cells/?L (immunoconcordant, n = 133) or <350 cells/?L (immunodiscordant, n = 95) were analyzed to evaluate the effect of CMV humoral response on immune recovery. In total, 27 HIV-uninfected individuals were included as controls. In addition, the presence of CMV IgM antibodies was retrospectively analyzed in 58 immunoconcordant individuals and 66 immunodiscordant individuals. Increased CMV IgG levels were observed in individuals with poor immune reconstitution (p = 0.0002). Increased CMV IgG responses were significantly correlated with lower nadir and absolute CD4+ T-cell counts. In contrast, CMV IgG responses were positively correlated with activation (HLA-DR+) and death markers in CD4+ T-cells and activated memory CD8+ T-cells (CD45RA-CD38+). Longitudinal subanalysis revealed an increased frequency of IgM+ samples in individuals with poor CD4+ T-cell recovery, and an association was observed between retrospective IgM positivity and the current level of IgG. The magnitude of the humoral immune response to CMV is associated with nadir CD4+ T-cell counts, inflammation, immune activation and CD4+ T-cell death, thus suggesting that CMV infection may be a relevant driving force in the increased morbidity/mortality observed in HIV+ individuals with poor CD4+ T-cell recovery.

| S-EPMC5608209 | biostudies-literature

Differential Gene Expression in HIV-Infected Individuals Following ART.

Project description:A paired analysis of peripheral blood mononuclear cells (PBMCs) isolated before and after antiretroviral therapy (ART) from a robust number of HIV-infected patients (N=36). Results identify a total of 4,157 DEGs following ART in HIV-infected participants and the transition from a period of active virus replication before ART to one of viral suppression This study evaluated PBMC gene expression in cells from 36 (4 dropped from analysis) recently HIV-infected individuals to identify differentially expressed genes following 48 weeks of ART

2013-09-10 | E-GEOD-44228 | biostudies-arrayexpress

Differential Gene Expression in HIV-Infected Individuals Following ART.

2013-09-10 | GSE44228 | GEO