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Published on: September 26, 2011
Clinical, Virological and Immunological Subphenotypes in a Cohort of Early Treated HIV-Infected Children
Sara Domínguez-Rodríguez1, Alfredo Tagarro1,2, Caroline Foster3
1Pediatric Infectious Diseases Unit, Fundación para la Investigación Biomédica del Hospital 12 de Octubre, Madrid, Spain.
Insights
Researchers identified three distinct subphenotypes in children with human immunodeficiency virus (HIV-1), offering new avenues for targeted therapies. These HIV subphenotypes show varying immune reconstitution and disease progression, guiding future cure-focused interventions.
Area of Science:
- Pediatric infectious diseases
- Immunology
- Virology
Background:
- Heterogeneous diseases like human immunodeficiency virus (HIV-1) may benefit from subphenotype identification for tailored therapeutic strategies.
- Understanding distinct patient groups is crucial for advancing treatment options in pediatric HIV-1.
Purpose of the Study:
- To classify pediatric HIV-1 patients into distinct subphenotypes based on clinical, virological, and immunological profiles.
- To identify potential biomarkers that differentiate these subphenotypes for future therapeutic guidance.
Main Methods:
- Collected comprehensive data including viral load, CD4/CD8 counts, HIV DNA reservoir size, immune cell subsets, and exhaustion markers.
- Employed unsupervised sparse clustering (lasso penalty) and hierarchical clustering (WARD.D2) for subphenotype identification.
- Validated clusters internally and compared characteristics using boxplots and Kruskal Wallis tests.
Main Results:
- Identified three distinct pediatric HIV-1 subphenotypes (Cluster 1: n=18, Cluster 2: n=11, Cluster 3: n=11).
- Cluster 1 showed favorable characteristics: earlier treatment, higher %CD4, lower HIV reservoir, higher TREC, and lower VCAM.
- Cluster 3 represented a less favorable profile: later treatment, lower %CD4, higher reservoir, increased CD8 senescence, lower TREC, higher VCAM, and higher %CD4 PD-1. Cluster 2 was intermediate.
Conclusions:
- Three pediatric HIV-1 subphenotypes with unique virological and immunological features were identified.
- The most favorable subphenotype exhibited enhanced immune reconstitution and slower progression, while the least favorable showed increased senescence and high viral reservoirs.
- These identified subphenotypes may guide future therapeutic interventions aimed at achieving a cure for HIV-1.
Background:
Identifying 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.
Methods:
We 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.
Results:
Three 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.
Conclusions:
Three 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.
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