Dataset Information

Virological and immunological outcome of treatment interruption in HIV-1-infected subjects vaccinated with MVA-B.

ABSTRACT: The most relevant endpoint in therapeutic HIV vaccination is the assessment of time to viral rebound or duration of sustained control of low-level viremia upon cART treatment cessation. Structured treatment interruptions (STI) are however not without risk to the patient and reliable predictors of viral rebound/control after therapeutic HIV-1 vaccination are urgently needed to ensure patient safety and guide therapeutic vaccine development. Here, we integrated immunological and virological parameters together with viral rebound dynamics after STI in a phase I therapeutic vaccine trial of a polyvalent MVA-B vaccine candidate to define predictors of viral control. Clinical parameters, proviral DNA, host HLA genetics and measures of humoral and cellular immunity were evaluated. A sieve effect analysis was conducted comparing pre-treatment viral sequences to breakthrough viruses after STI. Our results show that a reduced proviral HIV-1 DNA at study entry was independently associated with two virological parameters, delayed HIV-1 RNA rebound (p = 0.029) and lower peak viremia after treatment cessation (p = 0.019). Reduced peak viremia was also positively correlated with a decreased number of HLA class I allele associated polymorphisms in Gag sequences in the rebounding virus population (p = 0.012). Our findings suggest that proviral DNA levels and the number of HLA-associated Gag polymorphisms may have an impact on the clinical outcome of STI. Incorporation of these parameters in future therapeutic vaccine trials may guide refined immunogen design and help conduct safer STI approaches.

SUBMITTER: Rosas-Umbert M

PROVIDER: S-EPMC5617163 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Virological and immunological outcome of treatment interruption in HIV-1-infected subjects vaccinated with MVA-B.

Rosás-Umbert Miriam M Mothe Beatriz B Noguera-Julian Marc M Bellido Rocío R Puertas Maria C MC Carrillo Jorge J Rodriguez C C Perez-Alvarez Núria N Cobarsí Patricia P Gomez Carmen E CE Esteban Mariano M Jímenez Jose Luis JL García Felipe F Blanco Julià J Martinez-Picado Javier J Paredes Roger R Brander Christian C

PloS one 20170927 9

The most relevant endpoint in therapeutic HIV vaccination is the assessment of time to viral rebound or duration of sustained control of low-level viremia upon cART treatment cessation. Structured treatment interruptions (STI) are however not without risk to the patient and reliable predictors of viral rebound/control after therapeutic HIV-1 vaccination are urgently needed to ensure patient safety and guide therapeutic vaccine development. Here, we integrated immunological and virological parame ...[more]

PMID: 28953921

Similar Datasets

Project description:BackgroundIntroduction of antiretroviral therapy (ART) in sub-Saharan Africa was a hot debate due to many concerns about adherence, logistics and resistance. Currently, it has been significantly scaled up. However as the WHO clinico-immunological approaches for initiation and monitoring of ART in the region lacks viral load determination and drug resistance monitoring, HIV infected adults and children may be at risk for "unrecognized" virologic failure and the subsequent development of antiretroviral drug resistance. This study evaluates the virological efficacy and immunological recovery of HIV/AIDS patients under ART.MethodsConsecutive HIV-1 infected adults (N = 100) and children (N = 100) who have been receiving ART for up to 6 years at Gondar University Hospital, Ethiopia were enrolled following the WHO protocol for assessment of acquired drug resistance. Magnitude of viral suppression, genotypic drug resistance mutations and patterns of CD4+ T cell recovery were determined using standard virological and immunological methods.ResultsVirological suppression (HIV RNA < 40 copies/ml) was observed in 82 and 87% of adults and children on a median time of 24 months on ART, respectively. Mutation K103N conferring resistance to non nucleoside reverse transcriptase inhibitors and thymidine analogue mutations (M41L, L210W) were found only in one adult and child patient, respectively. Median CD4+ T cell count has increased from baseline 124 to 266 (IQR: 203-306) and 345 (IQR: 17-1435) to 998 (IQR: 678-2205) cells/mm3 in adults and children respectively after 12 months of ART. Nevertheless, small but significant number of clinically asymptomatic adults (16%) and children (13%) had low level viraemia (HIV-1 RNA 41-1000 copies/ml).ConclusionsMajority of both adults (82%) and children (87%) who received ART showed high viral suppression and immunological recovery. This indicates that despite limited resources in the setting virological efficacy can be sustained for a substantial length of time and also enhance immunological recovery irrespective of age. However, the presence of drug resistance mutations and low level viraemia among clinically asymptomatic patients highlights the need for virological monitoring.

Project description:BackgroundIdentifying subphenotypes within heterogeneous diseases may have an impact in terms of therapeutic options. In this study, we aim to assess different subphenotypes in children living with human immunodeficiency virus (HIV-1), according to the clinical, virological, and immunological characteristics.MethodsWe collected clinical and sociodemographic data, baseline viral load (VL), CD4 and CD8 count and percentage, age at initiation of ART, HIV DNA reservoir size in peripheral blood mononuclear cells (PBMCs), cell-associated RNA (CA-RNA), ultrasensitive VL, CD4 subsets (T effector CD25+, activated memory cells, Treg cells), humoral-specific HIV response (T-bet B cells), innate response (CD56dim natural killer (NK) cells, NKp46+, perforin), exhaustion markers (PD-1, PD-L1, DNAM), CD8 senescence, and biomarkers for T-lymphocyte thymic output (TREC) and endothelial activation (VCAM). The most informative variables were selected using an unsupervised lasso-type penalty selection for sparse clustering. Hierarchical clustering was performed using Pearson correlation as the distance metric and WARD.D2 as the clustering method. Internal validation was applied to select the best number of clusters. To compare the characteristics among clusters, boxplot and Kruskal Wallis test were assessed.ResultsThree subphenotypes were discovered (cluster1: n=18, 45%; cluster2: n=11, 27.5%; cluster3: n=11, 27.5%). Patients in cluster1 were treated earlier, had higher baseline %CD4, low HIV reservoir size, low western blot score, higher TREC values, and lower VCAM values than the patients in the other clusters. In contrast, cluster3 was the less favorable. Patients were treated later and presented poorer outcomes with lower %CD4, and higher reservoir size, along with a higher percentage of CD8 immunosenescent cells, lower TREC, higher VCAM cytokine, and a higher %CD4 PD-1. Cluster2 was intermediate. Patients were like those of cluster1, but had lower levels of t-bet expression and higher HIV DNA reservoir size.ConclusionsThree HIV pediatric subphenotypes with different virological and immunological features were identified. The most favorable cluster was characterized by a higher rate of immune reconstitution and a slower disease progression, and the less favorable with more senescence and high reservoir size. In the near future therapeutic interventions for a path of a cure might be guided or supported by the different subphenotypes.

Project description:BackgroundThe challenges of identifying acute HIV infection (AHI) have resulted in a lack of critical information on early AHI that constrains the development of therapeutics that are designed to eradicate HIV from the infected host.MethodsAHI participants were recruited from the Thai Red Cross Anonymous Clinic in Bangkok, Thailand into the RV254/SEARCH010 protocol and categorised according to Fiebig stages as follows: Fiebig I (HIV-RNA+, p24 Ag-, HIV IgM-) and Fiebig II-IV (HIV-RNA+, p24 Ag + or -, HIV IgM- or +, Western blot- or indeterminate). Proviral and viral burden and immune activation levels were compared between Fiebig stage groups at the time of AHI. CD4 and CD4/CD8 ratio were also compared between groups before and up to 96 weeks of ART.ResultsMedian age was 27 years and 96% were male. Fiebig I individuals had lower median HIV-DNA in mononuclear cells from blood (3 vs. 190 copies/106 cells) and gut (0 vs. 898 copies/106 cells), and lower HIV-RNA in blood (4.2 vs. 6.2 log10 copies/mL), gut (1.7 vs. 3.1 log10 copies/mg) and cerebrospinal fluid (2.0 vs. 3.8 log10 copies/mL), when compared to Fiebig II-IV individuals (all P<0.01). Median plasma sCD14 level was lower (1.1 vs. 1.6 μg/mL) in Fiebig I individuals as was the frequency of CD8+HLADR+CD38+ T cells in blood (7.6 vs. 14.9%, both P<0.05). The median plasma interleukin 6 levels were similar between stages (0.6 in Fiebig I vs. 0.5 pg/mL in Fiebig II-IV, P>0.05). The frequencies of CD4+HLA-DR+CD38+ T cells were also similar between these stages (2.1 vs. 2.6%, P>0.05). Median CD4 count and CD4/CD8 ratio were higher in Fiebig I: 508 vs. 340 cells/mm3 and 1.1 vs. 0.7, respectively (both P<0.001). After ART, CD4 cell count normalised by week 24 in Fiebig I and week 48 in Fiebig II-IV. However, CD4/CD8 ratio was lower in both groups after 96 weeks of ART compared to healthy Thais (P=0.02).ConclusionsCompared to later AHI stages, Fiebig I was associated with lower HIV burden in blood and tissue compartments, lower immune activation and higher CD4 and CD4/CD8 ratio. ART in Fiebig I-IV resulted in normalisation of CD4 cell count within the first year, supporting the benefit of early ART. However, the CD4/CD8 ratio was not normalised after 2 years of ART in all AHI stages, suggesting some degree of persistent immunological dysfunction even when ART was instituted as early as Fiebig I.

Dataset Information

Virological and immunological outcome of treatment interruption in HIV-1-infected subjects vaccinated with MVA-B.

Publications

Virological and immunological outcome of treatment interruption in HIV-1-infected subjects vaccinated with MVA-B.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets