Altered body fat repartition is common in HIV-infected patients under treatment. Although the occurrence of lipoatrophy was largely related to the use of thymidine nucleoside reverse transcriptase inhibitors (NRTIs) and in priority of stavudine (D4T), the occurrence of central fat accumulation was less clearly related to individual antiretroviral therapy (ART) molecules.1 Moreover, although the incidence of lipoatrophy has markedly decreased with the use of recently marketed drugs, the incidence of central fat accumulation is still important, even in patients recently initiated with ART,2 and the role of individual molecules is difficult to assign. Thus, the pathophysiology of central fat accumulation in HIV-infected patients remains poorly understood.
Obesity, outside HIV infection, is now considered as an inflammatory disease, adverted adipose tissue being able to release proinflammatory chemokines and cytokines with adverse metabolic and cardiovascular outcomes.3 Indeed, adipose tissue contains not only adipocytes but also stromal and vascular cells, such as fibroblasts, vascular endothelial cells, and immune cells including macrophages and lymphocytes. Activated macrophages are postulated to be essential for the production of proinflammatory chemokines and cytokines driving adipose tissue inflammation.4 However, it is still unclear how adipose inflammation is initiated and maintained. In animal models, CD8+ T-cell infiltration precedes accumulation of macrophages in adipose tissue of obese mouse. CD8+ T cells are required for adipose tissue inflammation and have major roles in macrophage differentiation, activation, and migration within adipose tissue. Conversely, CD4 T cells seem to be protective against inflammation and insulin resistance.4
In human studies, obesity was also reported to be associated with activated and insulin-resistant immune cell.5 In particular, the number of CD4 and CD8 T cells was found to be increased in subcutaneous adipose tissue (SAT) from obese subjects associated with an increased production of proinflammatory cytokines by CD8 lymphocytes while the role of CD4 cells is less clear.6,7 Visceral adipose tissue (VAT), liver fat and epicardial, the so-called ectopic fat depot is now considered metabolically very active, secreting proinflammatory cytokines and mediators at a higher rate than subcutaneous fat.8,9
Moreover, fat inflammation is now considered to be a crucial process leading to the metabolic syndrome, type 2 diabetes mellitus (T2DM), and atherosclerotic cardiovascular disease (CVD).3
The presence of an increased level of immune activation and/or inflammation, which can be identified with the expansion of CD8/CD38, has been reported in HIV-infected patients, even ART controlled,10 and has been linked with mortality and the occurrence of several non–AIDS-related comorbidities. Moreover, Paiardini et al11 showed that chronic immune activation is associated with a dysregulation of interleukin-7 (IL-7)/IL-7R system, which can be identified with the expansion of CD8CD127 T cells.
In the Strategies for Management of Anti-Retroviral Therapy (SMART) study, increased levels of the marker of innate immune activation sCD14 were related to increased mortality.12 An increased level of arterial inflammation was shown by using PET scan and was related to an increased level of the marker of innate immunity activation sCD163.13 Regarding T-cell activation, higher levels of CD8, an indirect marker of CD8 activation, were associated with an increased prevalence of myocardial infarction.14 Recently, increased levels of sCD14 were related to increased intima media thickness. Kaplan et al10 reported higher frequencies of activated CD4+ and CD8+ T cells in HIV-infected women compared with uninfected women whose frequencies were associated with increased prevalence of carotid artery lesions.
The possible relationship between immune dysfunction and lipodistrophy as a clinical entity or with its antropometric correlates, namenly VAT as a surrogate for central fat accumulation, has not been addressed in HIV-infected patients. VAT has been associated with T2DM and CVD events and with surrogate markers of cardiometabolic diseases including insulin resistance, evaluated by the homeostasis model of insulin resistance (HOMA-IR) test15 and coronary plaques burden, evaluated by the coronary artery calcium (CAC) score.16 Increased VAT is frequent in HIV-infected patients leading to a lipodystrophic phenotype of central fat accumulation [lipodystrophy (LD)], affecting presently almost half of ART-treated HIV-infected patients.2,17,18
The prevalence and incidence of T2DM and CVD are also higher in HIV-infected patients than in the general population.19–22
Therefore, our aim was to search for an association between peripheral activation/differentiation T-cell phenotypes and IL-7/IL-7R system expression/activation and clinical LD and VAT.
This was a cross-sectional observational study of 87 consecutive HIV-infected patients referred to the Metabolic Clinic of the University of Modena and Reggio Emilia (Italy) between January 2012 and June 2012. The study was approved by the local institutional review board (Comitato Etico Provinciale di Modena). Inclusion criteria were documented HIV infection, age >18 years, and stable ART for at least 6 months with undetectable HIV viremia (<40 copies/mL) except in 2 patients with a viral load of 60 and 118 copies per milliliter. Patients were excluded if they reported or had documented evidence of CVDs such as myocardial infarction, stroke or angina, end-stage liver or renal disease, or were on lipid-lowering therapy.
Clinical and Laboratory Variables
Demographic characteristics, HIV infection history, Centers for Disease Control classification, type and duration of ART including individual molecules [NRTI, D4T, zidovudine, non-NRTI, and protease inhibitor (PI)], and smoking were collected. Laboratory analyses included the following: plasma HIV-1 RNA, total cholesterol, low-density lipoprotein cholesterol, hight-density lipoprotein cholesterol, triglycerides, apolipoprotein A1, apolipoprotein B, blood glucose, and insulin. Insulin resistance was measured by the HOMA-IR index using the algorithm HOMA-IR = [(glucose, mmo/L) × (insulin, mU/L)]/22.5.
All patients underwent physical examination at the visit when a blood sample was taken. Waist circumference and height and body weight were measured by a single operator. Waist circumference was measured at the narrowest point halfway between the lowest rib and the iliac crest with the subject standing at the end of expiration. Body mass index was calculated as weight in kilograms divided by the square of height in meters. Clinical LD was defined using the HIV Outpatient Study definition, with anthropomorphic categorizations of lipoatrophy, lipohypertrophy, and mixed form.23 The presence of metabolic syndrome was diagnosed according to the clinical criteria proposed by the National Cholesterol Education Program-Adult Treatment Panel III.24 The Framingham risk score was calculated for each patient using the 2008 equations proposed by the Adult Treatment Panel III.25
CAC score was calculated according to the Agatston method as previously described.26 Because the CAC score was not normally distributed and its predictive power has been shown to be significantly increased for values greater than 10, this variable was dichotomized as greater or smaller than 10 and was chosen as a surrogate of CVD as previously described.27
Abdominal visceral adipose tissue (VAT), SAT, and total adipose tissue surface (TAT) were measured on a single-slice abdominal CT at the level of the L4 vertebra. VAT/TAT and SAT/VAT ratios were calculated, and VAT/TAT was used as a surrogate for central fat accumulation being a variable more strongly related to central fat accumulation than to obesity.28 The total estimated radiation dose for the chest and abdominal CT was 1.1 mSv.
Studies on the T-cell phenotypes and of the expression of the IL-7/IL-7R system were performed at the laboratory of clinical analyses, San Paolo Hospital, Milan.
T-cell count (CD3+CD4/CD8) and T-cell activation, maturation, and IL-7Rα (CD127) cell surface expression were evaluated by cytometry on fresh peripheral blood mononuclear cell (PBMC) using the following fluorochrome-labeled monoclonal antibodies: CD38-FITC, CD45RA-FITC, CD4-PerPC-Cy5.5, and CD8-PerPC-Cy5.5 (BD Biosciences, San Jose, CA); CD4-Pcy7, CD8-APC, and CD127-PE (Beckman Coulter, Hialeah, FL); and CCR7-PE (R&D, Milan, Italy). The following combinations were used: CD4/CD8/CD127 (IL-7R expression), CD8/CD38 (activated), CCR7+/CD45RA+/CD4/CD8 (naive), CCR7+/CD45RA−/CD4/CD8 (central memory), CCR7−/CD45RA+/CD4/CD8 (terminally differentiated), and CCR7−/CD45RA−/CD4/CD8 (effector memory). Analyses were conducted by Cytomics FC500 (Beckman Coulter).
IL-7 Plasma Concentration
IL-7 plasma concentration was evaluated by standard ELISA assay (Quantikine HS human IL-7; R&D) according to the manufacturer’s instructions.
Assessment of Stat-5 Phosphorylation
Ficoll-separated PBMCs were stained with surface fluorescent directly labeled antibodies (CD4-FITC, CD8-FITC, Becton Dickinson, San Josè, CA). PBMCs (2 × 206 cells) were incubated in medium (serum-free RPMI) with or without IL-7 (20 ng/mL) for 25 minutes at 37°C, washed, fixed, permeabilized, and stained with anti-pStat-5 PerCP-Cy5.5 (BD Biosciences) for 2 hours at room temperature in the dark. The following combinations of monoclonal antibodies were used: CD4/pStat-5 and CD8/pStat-5.
Variables are expressed as median and interquartile range (IQR) for continuous variables and as frequencies and percentage for categorical variables.
The association between clinical LD and VAT/TAT with peripheral T-lymphocytes phenotypes was explored in univariate analyses (Mann–Whitney U test).
Immune phenotypes, which were significantly associated in univariate analyses, were included as covariates, after correction for sex and age, in separate multivariables models for the prediction of lipoatrophy or central fat accumulation versus no LD and VAT/TAT.
We also calculated the association between VAT/TAT and HOMA-IR and CAC score >10, respectively, used as surrogate markers for the risk of T2DM and CVD.
Patients’ Characteristics Based on Clinical LD
Patients’ characteristics based on the presence of clinical LD are presented in Table 1. Most patients were male, middle aged (49 years) exposed to HIV for a long time (known duration of infection 231 months), and with high CD4 cell count (653/μL). The most commonly used ART regimens were 2NRTI + non-NRTI (40.8%) and 2NRTI + PI/r (30.6%). Most common backbones are TDF/FTC (46.9%) and ABC/3TC (20.4%).
Per protocol, all patients except 2 had undetectable viral load. LD was diagnosed in 72% of patients: 32% of them had lipoatrophy and 40% central fat accumulation (lipohypertrophy and mixed form considered together). The prevalence of metabolic syndrome was 24%. Regarding the HIV characteristics, patients with lipoatrophy had a longer known duration of HIV infection, a lowed nadir CD4 value, a longer time of exposure to PI and NRTI. Moreover, patients with lipoatrophy had a longer time of exposure to D4T. As expected, the anthropometric markers including body mass index, waist circumference, SAT and TAT, confirmed the lipodystrophic phenotype either lipoatrophy or central fat accumulation. However, the VAT values were not different between the groups.
The study population showed the following immune phenotypes for T lymphocytes [median percentage (IQR)]: CD8+CD38+ = 7.50 (4–23.25), CD4+CD127+ = 65 (55–75.25), CD8+CD127+ = 57.5 (49–68), CD4/pStat-5 = 0.3 (−0.8 to 2.25), CD8/pStat-5 = 0.4 (−0.5 to 2.5), and IL-7 (ρg/mL) = 22.2 (7.9–24.4).
CD8 T-Cell Activation and Expression of IL-7R Is Associated With Clinical LD
Table S1 (see Supplemental Digital Content, http://links.lww.com/QAI/A465) shows the characteristics of CD4+ and CD8+ T-cell immune phenotypes according to the clinical LD.
Compared with no LD, patients with central fat accumulation displayed a higher proportion of CD38-expressing CD8 cells (median, IQR: no LD: 6, 3–10 and central fat accumulation: 8, 6–12; P = 0.005; Fig. 1A). The expression of CD38 on CD8+ cells was significantly higher also when we compared no LD with lipoatrophy (median, IQR: no LD: 6, 3–10 and lipoatrophy: 9, 5–14; P = 0.025; Fig. 1A).
Regarding the IL-7/IL-7R system and signaling, patients with lipoatrophy and central fat accumulation were characterized by higher proportions of CD8+CD127+ T cells in comparison with patient with no LD (median, IQR: no LD: 50, 43–55; lipoatrophy: 61, 54–73; and central fat accumulation: 61, 49–68; P = 0.002 and 0.008, respectively; Fig. 1B). We did not observe differences based on the absence or presence of LD when considering plasma levels of IL-7 and the IL-7 transcription signal evaluated by the level of Stat-5 phosphorylation. Plasma IL-7 levels (median, IQR) were 22.3, 8.2–23.6 pg/mL for no LD; 22.4, 5.8–25.2 pg/mL for lipoatrophy; and 22.9, 7.6–25 pg/mL for central fat accumulation (P value not significant in group comparison). Stat-5/CD8 (median, IQR) were 0.2, −0.3 to 2.2 for no LD; 0.3, −2.2 to 2.5 for lipoatrophy; and 0.5, −0.5 to 2.7 for central fat accumulation (P value not significant in group comparison).
Immune phenotypes that were different according to the lipodystrophic phenotype in univariate analyses were included in a multivariable model to explore the risk prediction of lipoatrophy or central fat accumulation versus no LD after adjusting for sex and age (Table 2). Both lipoatrophy and central fat accumulation were associated with CD8+ T-cell activation and IL-7R expression, respectively, CD8+CD38+ T cells and CD8+C127+ T cells. Nevertheless, the dysregulation of 1 of the 2 immunologic phenotypes is not able to discern between the LD phenotype.
CD8 T-Cell Activation Is Associated With Relative VAT Amount
Table S2 (see Supplemental Digital Content, http://links.lww.com/QAI/A465) shows the characteristics of the immune phenotypes according to VAT/TAT and SAT/VAT ratios. Activated CD8+CD38+ T cells were associated with the VAT/TAT ratio and inversely related to the SAT/VAT ratio. There was no association with the CD8+CD127+ phenotype.
No differentiation or maturation phenotypes nor IL-7 plasma level or transcription signal were associated with VAT ratios.
A multivariate analysis was performed to correlate outcomes and predictors after adjusting for sex and age (Table 3). The analysis confirmed the positive association between CD8+CD38+ T cells and the VAT/TAT ratio and the negative association with the SAT/VAT ratio.
Association of VAT/TAT to Cardiometabolic Outcomes
As expected, the VAT/TAT ratio was correlated with HOMA-IR (r = 0.364, P = 0.028). It was also correlated with CAC > 10 (r = 0.406, P = 0.002) in favor of an increased cardiometabolic risk mediated by the VAT amount.
This study established the presence of a relationship between T-cell phenotypes and adiposity in ART-treated HIV-infected patients. We observed that both clinical LD and anthropometric measurement of visceral fat amounts were associated with peripheral CD8 T-cell activation, suggesting that CD8 activation could be involved in central fat accumulation, in particular in VAT amount. We also confirmed the association between VAT and insulin resistance as a predictor of type 2 diabetes and CAC as a cardiovascular risk factor.
The setting in which this study was performed is an outpatient HIV clinic in which most of the attendees have undetectable viral load, obtained a satisfactory level of immune reconstitution and have a low CVD risk profile, as assessed by Framingham Risk score (Table 1). Most of these patients showed clinical signs of LD. No information relating to the duration of LD or the activation T-cell phenotypes changes at the onset of LD were possible to obtain due to the cross-sectional observation. Therefore, such a population represents an adequate group to explore the potential relationships between T-cell immune phenotypes and fat accumulation.
We characterized our population both for clinical LD and for VAT quantification. This choice was due to the current changing pattern of clinical LD moving from lipoatrophy to a central fat accumulation phenotype. Lipoatrophy has been proven to be linked to mitochondrial damage secondary to cumulative thymidine analogue exposure (mainly D4T and zidovudine) and to low nadir CD4 cells count.23,29 On the other hand, lipohypertrophy does not clearly seem to be associated with ART drug classes exposure nor with CD4 cells count nor in this casuistic nor in HIV literature.18 Central fat accumulation could mimic in part the anthropometric changes observed in physiological aging and age is a recognized risk factor. However, other factors are probably involved. We postulated that immune dysfunction could be one of these factors.
We have previously shown a close relationship between central fat accumulation or mixed LD and VAT,27 and this was also confirmed in this data set (Table 1).
VAT/TAT variable was generated to correct impact of overall adiposity on visceral fat deposition.
We identified CD8+CD38+ T-cell and CD8+CD127+ T-cell phenotypes as being associated with lipoatrophy and central fat accumulation. Despite the fact that HIV replication has been identified as the main driving force for CD8+ T-cell activation,30 increased activation persists in treated patients with restored CD4 levels and suppressed viral load.10 Increased immune activation and chronic inflammation identified in these patients have been suggested to result in part from the disruption of the gut mucosal barrier and persistent translocation of bacterial products31,32 and from chronic CMV or HCV replication.33,34 Other factors, HIV linked or not, may also be involved.35 The role of CD8 activation in long-term complications observed in HIV-infected patients has been recently outlined by Kaplan et al36 who showed an association between CD8 activation and subclinical carotid artery disease and carotid artery stiffness among HIV-infected women.
Regarding the expression of the IL-7R, we observed that LD was associated with an increased proportion of CD8+CD127+ T cells, a phenotype presented as a central memory phenotype able to proliferate, and a marker of immune reconstitution.11,37,38 However, the level of IL-7 and IL-7R activation, as evaluated by the level of Stat-5 phosphorylation, was not modified based on clinical LD. Therefore, there was no evident activation of the IL-7/IL-7R system. The relationship with LD is not obvious and requires further investigation.
Recent studies have documented the ability of abdominal adipose tissue, in particular in the visceral location, to generate inflammatory mediators. In addition to the inherent properties of fat cells in energy management and metabolic homeostasis, adipose tissue serves as a key site for the interaction of adipocytes with other effectors of the immune system. There are also striking commonalities between adipocytes and a diverse set of immune cells (including T cells, macrophages, and dendritic cells).
It is still unclear how adipose inflammation is initiated and maintained. In animal models, CD8+ T-cell infiltration precedes accumulation of macrophages in adipose tissue obesity. Furthermore, CD8+ T cells are required for adipose tissue inflammation, and they have major roles in macrophage differentiation, activation, and migration. Thus, CD8+ T cells are crucially involved in initiating inflammatory cascades in obese adipose tissue.4 Such studies suggest ectopic fat as a central and primary player and as both a source and a site of inflammation with immune activation and chronic inflammation being drivers of ectopic fat accumulation.
This study has several limitations as follows: the cross-sectional structure, the lack of control group, and the absence of clinical hard endpoints allow to prove neither a pathogenic link between immune activation and adipose tissue deposition nor an association of the latter with T2DM and CVD. We did not study T-cell immune phenotypes within the adipose tissue stroma because our samples were obtained at the systemic level.
In conclusion, our data provide further evidence that in HIV-infected patients, ART-controlled, CD8+ T-cell activation may reveal a potential link with LD and VAT accumulation, which represents a strong cardiometabolic risk factor.
The authors are grateful to all patients and their families for participating in the study. Special thanks to E. Garlassi who revised the manuscript. They would like to acknowledge all the staff for their precious help throughout the study: in particular, Dr G. Orlando and Dr F. Carli were responsible for the clinical care of the patients, Dr M. Menozzi and Dr P. Bagni provided logistic contribution in the management of the biobank.
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