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Published on: May 30, 2013
Antiretroviral therapy suppressed participants with low CD4+ T-cell counts segregate according to opposite
Josué Pérez-Santiago1, Dan Ouchi, Victor Urrea
1aUniversity of California San Diego, La Jolla, California, USAbInstitut de Recerca de la Sida IrsiCaixa-HIVACAT, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, UAB, BadalonacUniversitat de Vic - Universitat Central de Catalunya, BarcelonadFundació Lluita contra la SIDA, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona, SpaineDepartment of Microbiology, Infectiology and Immunology, Université de Montréal, Faculté de MédecinefCentre de Recherche du CHUM, Montréal, Québec, Canada.
Insights
A CD4 T-cell count cutoff of 400 cells/μl best identifies immunodiscordance in HIV patients. This immunodiscordance shows diverse immune patterns, aiding personalized treatment strategies for better CD4 T-cell recovery.
Area of Science:
- Immunology
- HIV/AIDS Research
- Cellular Biology
Background:
- Immunodiscordance, characterized by a failure to increase CD4 T-cell counts despite antiretroviral therapy (ART) suppression, is linked to disrupted CD4 T-cell homeostasis and affects clinical outcomes in HIV-infected individuals.
- Understanding the immunological underpinnings of immunodiscordance is crucial for improving patient management and therapeutic strategies.
Purpose of the Study:
- To evaluate different definitions of immunodiscordance based on CD4 T-cell counts and increases from nadir.
- To identify immunological and clinical variables that distinguish immunodiscordant from immunoconcordant individuals.
- To explore the heterogeneity within the immunodiscordant group using unsupervised clustering.
Main Methods:
- Supervised random forest classification was employed to analyze 74 immunological and clinical variables in 196 ART-suppressed individuals.
- Unsupervised clustering was performed on relevant variables identified from the supervised analysis in 191 individuals.
- Various CD4 T-cell count cutoffs and increases from nadir (ΔCD4) were assessed for their ability to define immunodiscordance.
Main Results:
- A CD4 T-cell count cutoff of 400 cells/μl achieved 85% accuracy in segregating immunodiscordant from immunoconcordant individuals, outperforming ΔCD4 definitions.
- Unsupervised clustering revealed significant heterogeneity among immunodiscordant individuals, identifying three distinct subgroups with varying T-cell activation, programmed cell-death protein-1 (PD-1) expression, and death rates.
- A notable subset (22%) of immunodiscordant individuals exhibited characteristics similar to immunoconcordant individuals, including high recent thymic emigrants and low CD4 T-cell activation/death, despite persistently low CD4 counts.
- Human leukocyte antigen - antigen D related (HLA-DR), PD-1, and CD45RA expression on CD4 T cells effectively reproduced subgroup segregation with 81.4% accuracy.
Conclusions:
- A CD4 T-cell count threshold of 400 cells/μl is a superior metric for classifying immunodiscordance compared to ΔCD4 measures.
- Immunodiscordance can manifest with diverse and even opposing immunological profiles, detectable through routine immunological monitoring.
- Subgroup classification based on immunological markers can guide clinicians in developing tailored strategies to enhance CD4 T-cell recovery in ART-suppressed individuals.
Background:
The failure to increase CD4 T-cell counts in some antiretroviral therapy suppressed participants (immunodiscordance) has been related to perturbed CD4 T-cell homeostasis and impacts clinical evolution.
Methods:
We evaluated different definitions of immunodiscordance based on CD4 T-cell counts (cutoff) or CD4 T-cell increases from nadir value (ΔCD4) using supervised random forest classification of 74 immunological and clinical variables from 196 antiretroviral therapy suppressed individuals. Unsupervised clustering was performed using relevant variables identified in the supervised approach from 191 individuals.
Results:
Cutoff definition of CD4 cell count 400 cells/μl performed better than any other definition in segregating immunoconcordant and immunodiscordant individuals (85% accuracy), using markers of activation, nadir and death of CD4 T cells. Unsupervised clustering of relevant variables using this definition revealed large heterogeneity between immunodiscordant individuals and segregated participants into three distinct subgroups with distinct production, programmed cell-death protein-1 (PD-1) expression, activation and death of T cells. Surprisingly, a nonnegligible number of immunodiscordant participants (22%) showed high frequency of recent thymic emigrants and low CD4 T-cell activation and death, very similar to immunoconcordant participants. Notably, human leukocyte antigen - antigen D related (HLA-DR) PD-1 and CD45RA expression in CD4 T cells allowed reproducing subgroup segregation (81.4% accuracy). Despite sharp immunological differences, similar and persistently low CD4 values were maintained in these participants over time.
Conclusion:
A cutoff value of CD4 T-cell count 400 cells/μl classified better immunodiscordant and immunoconcordant individuals than any ΔCD4 classification. Immunodiscordance may present several, even opposite, immunological patterns that are identified by a simple immunological follow-up. Subgroup classification may help clinicians to delineate diverse approaches that may be needed to boost CD4 T-cell recovery.
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