Adipokines as New Biomarkers of Immune Recovery: Apelin Receptor, RBP4 and ZAG Are Related to CD4+ T-Cell Reconstitution in PLHIV on Suppressive Antiretroviral Therapy.

Elena Yeregui,Montserrat Vargas,Jenifer Masip,Julià Blanco,Verónica Alba,Yolanda M Pacheco,Joaquim Peraire,Anna Rull,Laia Reverté,Manuel Leal,Consuelo Viladés,Anna Martí,Francesc Vidal,Eugènia Negredo,Ma Montserrat Olona Cabases ,Judit Vidal‐González ,María Peraire ,Frederic Gómez ,Graciano García‐Pardo ,Peré Domingo ,Josép Mallolas

doi:10.3390/ijms23042202

Abstract

A significant proportion of people living with HIV (PLHIV) who successfully achieve virological suppression fail to recover CD4+ T-cell counts. Since adipose tissue has been discovered as a key immune organ, this study aimed to assess the role of adipokines in the HIV immunodiscordant response. This is a multicenter prospective study including 221 PLHIV starting the first antiretroviral therapy (ART) and classified according to baseline CD4+ T-cell counts/µL (controls > 200 cells/µL and cases ≤ 200 cells/µL). Immune failure recovery was considered when cases did not reach more than 250 CD4+ T cells/µL at 144 weeks (immunological nonresponders, INR). Circulating adipokine concentrations were longitudinally measured using enzyme-linked immunosorbent assays. At baseline, apelin receptor (APLNR) and zinc-alpha-2-glycoprotein (ZAG) concentrations were significantly lower in INRs than in immunological responders (p = 0.043 and p = 0.034), and they remained lower during all ART follow-up visits (p = 0.044 and p = 0.028 for APLNR, p = 0.038 and p = 0.010 for ZAG, at 48 and 144 weeks, respectively). ZAG levels positively correlated with retinol-binding protein 4 (RBP4) levels (p < 0.01), and low circulating RBP4 concentrations were related to a low CD4+ T-cell gain (p = 0.018 and p = 0.039 at 48 and 144 weeks, respectively). Multiple regression adjusted for clinical variables and adipokine concentrations confirmed both low APLNR and RBP4 as independent predictors for CD4+ T cells at 144 weeks (p < 0.001). In conclusion, low APLNR and RBP4 concentrations were associated with poor immune recovery in treated PLHIV and could be considered predictive biomarkers of a discordant immunological response.

Highlights

Since the introduction of effective antiretroviral therapy (ART), the morbidity and mortality of people who live with HIV infection (PLHIV) has drastically decreased
Adipose tissue has been advanced as a potential HIV reservoir, and viral persistence in adipose tissue after ART initiation might be related to the metabolic and immune dysfunctions of adipose tissue cells [22,23]
In this study, we postulated that low baseline circulating apelin receptor and ZAG concentrations were related to low CD4+ T-cell reconstitution (CD4+ T cell at 144 weeks) in PLHIV on ART and that their persistent low concentrations were related to poor immune progression

Summary

Introduction

Since the introduction of effective antiretroviral therapy (ART), the morbidity and mortality of people who live with HIV infection (PLHIV) has drastically decreased. In previous years, several investigations have been conducted regarding adipose tissue and its role in HIV, concretely in ART-induced lipodystrophy and metabolic disturbances [13,14,15,16]. Adipose tissue has been advanced as a potential HIV reservoir, and viral persistence in adipose tissue after ART initiation might be related to the metabolic and immune dysfunctions of adipose tissue cells [22,23]. In this regard, we hypothesized that the secretion of adipokines, hormones with immunomodulatory effects secreted by adipocytes [10,24,25,26,27], may be related to CD4+ T cell depletion and restoration in PLHIV. We aimed to relate plasma adipokine concentrations to nadir CD4+ T cell counts and to anticipate poor immune recovery using circulating adipokines as potential biomarkers

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Discussion

Conclusion