TY - JOUR
T1 - Alterations in circulating immunoregulatory proteins discriminate poor CD4 T lymphocyte trajectories in people with HIV on suppressive antiretroviral therapy
AU - Moar, Preeti
AU - Bowler, Scott
AU - Landay, Alan L.
AU - Gianella, Sara
AU - Ndhlovu, Lishomwa C.
AU - Premeaux, Thomas A.
N1 - Publisher Copyright:
© 2024 Moar et al.
PY - 2024/10
Y1 - 2024/10
N2 - Despite the success in the management of HIV with antiretroviral therapy (ART), people with HIV (PWH) have a heightened state of immune activation and inflammation,and an estimated 10%-40% demonstrate poor CD4 T-cell reconstitution, thereby increasing their mortality and morbidity risk burden. Soluble immunoregulatory proteins that function in lymphocyte activation or inhibition are elevated in PWH and associate with T-cell dysfunction, HIV persistence, and are predictive of comorbid outcomes. Here, we measured a panel of 35 circulating immunoregulatory proteins in 116 PWH with variations in CD4 T-cell counts (poor CD4 trajectory: <200 cells/μl, n = 34 or immune competent: CD4 >500 cells/μl, n = 82) by Luminex. Participants were enrolled in the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort, had initiated ART on enrollment, and had been on suppressive ART for 1 year. Using non-parametric analysis, we found that the levels of CD276, ICOSL, BAFF, OX40, galectin-1, and galectin-9 were significantlyhigher in PWH with poor CD4 trajectories compared to individuals with immune-competent CD4 T-cell count. Notably, in logistic models, ICOSL and OX40 remained significantafter adjusting for age and baseline plasma HIV RNA. Furthermore, Extreme Gradient Boosting machine learning models comprising co-stimulatory and inhibitory checkpoint proteins yielded high accuracy in classificationof individuals with poor CD4 trajectories. In summary, we identifieda novel signature of circulating immunoregulatory proteins indicative of poor CD4 trajectories that may serve as potential targets to monitor and manage immune perturbations more accurately in PWH during suppressive ART. IMPORTANCE It is essential to track immune perturbations related to insufficientCD4 T-cell recovery in PWH on suppressive ART as those with incomplete reconstitution are at a greater risk of non-AIDS-related morbidity and mortality. Several inflammatorysoluble mediators have associated with poor immune reconstitution and adverse morbid outcomes in PWH, yet their implementation into routine clinical care to guide management remains inconsistent. Circulating immune checkpoint proteins have been linked to dysregulated immune pathways during suppressive ART and may serve as improved surrogate markers of clinical relevance. Here we investigate soluble lymphocyte-associated immunoregulatory proteins in virally suppressed PWH with no reported co-morbid outcomes and varying CD4 T-cell counts, to reveal underlying pathways that remain perturbed despite ART. This novel signature of immunoregulatory markers pertaining to poor CD4 T-cell trajectories uncover previously overlooked immune checkpoints as important targets for clinical monitoring of PWH in the setting of durable viral suppression by ART.
AB - Despite the success in the management of HIV with antiretroviral therapy (ART), people with HIV (PWH) have a heightened state of immune activation and inflammation,and an estimated 10%-40% demonstrate poor CD4 T-cell reconstitution, thereby increasing their mortality and morbidity risk burden. Soluble immunoregulatory proteins that function in lymphocyte activation or inhibition are elevated in PWH and associate with T-cell dysfunction, HIV persistence, and are predictive of comorbid outcomes. Here, we measured a panel of 35 circulating immunoregulatory proteins in 116 PWH with variations in CD4 T-cell counts (poor CD4 trajectory: <200 cells/μl, n = 34 or immune competent: CD4 >500 cells/μl, n = 82) by Luminex. Participants were enrolled in the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort, had initiated ART on enrollment, and had been on suppressive ART for 1 year. Using non-parametric analysis, we found that the levels of CD276, ICOSL, BAFF, OX40, galectin-1, and galectin-9 were significantlyhigher in PWH with poor CD4 trajectories compared to individuals with immune-competent CD4 T-cell count. Notably, in logistic models, ICOSL and OX40 remained significantafter adjusting for age and baseline plasma HIV RNA. Furthermore, Extreme Gradient Boosting machine learning models comprising co-stimulatory and inhibitory checkpoint proteins yielded high accuracy in classificationof individuals with poor CD4 trajectories. In summary, we identifieda novel signature of circulating immunoregulatory proteins indicative of poor CD4 trajectories that may serve as potential targets to monitor and manage immune perturbations more accurately in PWH during suppressive ART. IMPORTANCE It is essential to track immune perturbations related to insufficientCD4 T-cell recovery in PWH on suppressive ART as those with incomplete reconstitution are at a greater risk of non-AIDS-related morbidity and mortality. Several inflammatorysoluble mediators have associated with poor immune reconstitution and adverse morbid outcomes in PWH, yet their implementation into routine clinical care to guide management remains inconsistent. Circulating immune checkpoint proteins have been linked to dysregulated immune pathways during suppressive ART and may serve as improved surrogate markers of clinical relevance. Here we investigate soluble lymphocyte-associated immunoregulatory proteins in virally suppressed PWH with no reported co-morbid outcomes and varying CD4 T-cell counts, to reveal underlying pathways that remain perturbed despite ART. This novel signature of immunoregulatory markers pertaining to poor CD4 T-cell trajectories uncover previously overlooked immune checkpoints as important targets for clinical monitoring of PWH in the setting of durable viral suppression by ART.
KW - CD4 lymphocytes
KW - composite biomarkers
KW - HIV pathogenesis
KW - immune checkpoints
KW - immune reconstitution
KW - machine learning
UR - http://www.scopus.com/inward/record.url?scp=85206958653&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85206958653&partnerID=8YFLogxK
U2 - 10.1128/mbio.02265-24
DO - 10.1128/mbio.02265-24
M3 - Article
C2 - 39287441
AN - SCOPUS:85206958653
SN - 2161-2129
VL - 15
JO - mBio
JF - mBio
IS - 10
ER -