HIV type 1 (HIV-1) infection is characterized by a chronic state of systemic inflammation and immune (T cell and macrophage/monocyte; M/M) activation that is an independent predictor of disease progression. Many of these changes do not normalize despite antiretroviral therapy (ART) [1,2]. This residual immune activation may be largely responsible for the increased morbidity and mortality observed in HIV-infected patients on ART but the exact mechanisms are unclear [1,2].
Oxidative stress is involved in pathogenesis of inflammatory diseases  and may impair antiviral immune responses . Lipids play key roles in both viral replication  and T-cell biology . During oxidative stress, oxidized phospholipids acquire novel biological activities such as the ability to regulate innate  and adaptive immunity [8,9] and pathogenesis of many diseases including cardiovascular disease (CVD) [10,11]. Modified lipoproteins such as oxidized LDL (LDLox) carry oxidized lipids and have pleomorphic atherogenic effects .
Although HDL is generally an anti-inflammatory lipoprotein with protective effects against oxidized lipids and CVD and major immunoregulatory function , during systemic inflammation it can be oxidized HDL (HDLox), becomes dysfunctional [13,14] and may contribute to CVD in patients with inflammation . We have shown that HIV-infected patients have HDLox, demonstrated by impaired antioxidant function and increased lipid hydroperoxide content [14–17] that is associated with measures of subclinical atherosclerosis such as carotid intima–media thickness (IMT)  and percentage noncalcified coronary plaque . In addition, modified lipoproteins may also directly accelerate immune dysfunction and senescence/exhaustion [19,20], that may contribute to multiple disorders  such as CVD . We  and others  have shown that oxidized lipoproteins directly upregulate immune activation in vitro. However, the exact role of oxidized lipoproteins in HIV pathogenesis is unclear. We hypothesize that there is a cycle of HIV-induced immune activation, inflammation, production of oxidized lipoproteins, and further immune activation and senescence. To elucidate this hypothesis, the objective of this study is to investigate in vivo whether oxidized lipoproteins (HDLox and LDLox) are positively associated with markers of inflammation [high-sensitivity C-reactive protein (hs-CRP); IL-6 and D-dimer], immune activation (such as sCD14, sCD163, human leukocyte antigen-D related (HLA-DR), CD38 expression on CD8+ T lymphocytes) and T-cell senescence (CD28 and CD57), and to evaluate how these relationships change over time during successful ART.
We evaluated HDLox and LDLox in samples from the AIDS Clinical Trials Group A5260s, a prospective study that longitudinally evaluated the changes in biomarkers of inflammation, immunosenescence and immune activation among treatment-naive individuals undergoing randomized ART initiation with an integrase-based regimen containing raltegravir (RAL) or a protease inhibitor-based regimen containing either atazanavir/ritonavir (ATV/r) or darunavir/ritonavir (DRV/r) . This prospective study revealed an overall increase in levels of LDLox and decrease in levels of HDLox markers of inflammation, coagulation, immune activation, CD4+ T-cell senescence and exhaustion, and CD8+ T-cell exhaustion (but not senescence), which were similar between the different ART regimens after 96 weeks of treatment . Following up on these data, we examined potential associations of plasma-oxidized lipoprotein levels with markers of systemic inflammation, coagulation and immune activation in these individuals.
Study design and participants
The design of A5260 and the virologic, tolerability and metabolic outcomes of these ART regimens have been previously reported [25–27]. The parent study and substudy were approved by the Institutional Review Boards at all participating institutions, and all patients provided written informed consent. For this analysis, the A5260s population was restricted to the subset of virologically suppressed individuals with no ART interruptions greater than 7 days and who achieved HIV RNA suppression less than 50 copies/ml by study week 24 and thereafter.
Determination of biomarkers and plasma-oxidized lipoproteins
Blood samples were drawn at study entry prior to ART initiation and at 24, 48, 96 and 144 weeks on treatment from participants who were required to fast for at least 8 h. Plasma biomarkers of systemic inflammation (IL-6, hs-CRP and D-dimer), M/M activation (sCD14 and sCD163) and T-cell activation [soluble IL-2 receptor (sIL-2r)], cellular markers of monocyte (CD163) and T-cell (HLA-DR and CD38) activation as well as inflammatory monocyte subsets (nonclassical CD14dim/CD16+ and intermediate CD14+CD16+) have previously been described in this cohort . LDLox was quantified using enzyme linked immunosorbent assay (Mercodia AB, Uppsala, Sweden) according to the manufacturer instructions. We also determined the LDLox/LDL oxidation ratio which may be a better marker of in-vivo oxidation of LDL compared with total levels of LDLox. HDLox was determined using a validated fluorometric cell-free biochemical assay that measures HDL lipid peroxidation (HDLox) . To reduce experimental variability  and adjust for HDL amount, we normalized the mean fluorescence readout from quadruplicates of each HDLox sample (HDLox_sample) by the mean fluorescence readout from quadruplicates of a pooled plasma HDLox control (HDLox_control) and by concurrent HDL-cholesterol (HDL-C) concentration level using the following calculation: ‘normalized’ HDLox (nHDLox) = [HDLox_sample × 40 (mg/dl)]/[HDLox_control × HDL-Csample (mg/dl)], in which 40 mg/dl represents HDL-C of the pooled plasma control. This approach has been validated in clinical studies [14,29–32]. Throughout the results section, HDLox is presented as nHDLox measure to reflect the adjustment for experimental variability and HDL-C.
Biomarkers were analyzed at study entry (baseline) and further examined at weeks 24 (cellular markers), 48 (plasma markers) and 96. Because of substantial skewness in the variables, a log transformation was used. Changes from baseline were reported as fold-changes, with the 95% confidence interval indicating a statistically significant change at the P less than 0.05 level. Associations of oxidized lipoproteins and markers of inflammation, immune activation and senescence were examined cross-sectionally prior to (entry) and on ART (week 96) and longitudinally (as fold-change from baseline) using Spearman (partial) correlations that adjusted for the covariates of age, sex, race, BMI, smoking status, baseline CD4+ cell count and baseline viral load. A Spearman partial correlation is similar to its Pearson partial correlation analog, except that all the variables are represented as their fractional ranks instead of being in their original units. To calculate the Spearman partial correlation, the covariates (as fractional ranks) are partialed out of two variables of interest, also expressed as ranks. The Pearson correlation between the residuals for the two variables is then the Spearman partial correlation coefficient. This value represents the unique independent effects of the oxidized lipoproteins on the makers of interest. For each set of hypotheses in the multivariate analysis (i.e. each table), the false discovery rate (FDR) was controlled at alpha = 0.05 using the Benjamini–Hochberg procedure . Statistical hypothesis tests were two-sided with a significance threshold of 0.05 for P values. All analyses were performed with Stata, version 13.1 (Stata Corp LP, College Station, Texas, USA).
Baseline demographic characteristics of the 328 patients from the A5260s study population and the 234 patients (71%) included in the virologically suppressed population for this analysis were previously described [25,27]. There were no differences in baseline demographic characteristics among treatment groups. Median age was 36 years, 90% of patients were men and 48% white. Median CD4+ cell count and median HIV RNA were 338 cells/μl and 4.6 log10 copies/ml, respectively.
Changes over time in plasma levels of oxidized lipoproteins
Changes over time in plasma levels of lipoproteins and oxidized lipoproteins are shown in Table 1. Briefly, HDL-C and LDL-cholesterol levels increased over time in all ART-treated individuals. Levels of normalized HDLox declined over week 96 of ART. Postbaseline levels of LDLox and LDLox/LDL increased over 24 weeks and remained elevated compared with baseline levels over 96 weeks of ART.
Relationship between oxidized lipoproteins with markers of inflammation, coagulation and immune activation in antiretroviral therapy–naive individuals
We found that nHDLox was positively associated with plasma biomarkers of inflammation (IL-6 and hs-CRP) and both higher nHDLox and LDLox/LDL were associated with higher coagulation (D-dimer) at entry prior to ART (Supplemental Table 1, https://links.lww.com/QAD/A975) (Fig. 1). The strongest relationships between oxidized lipoproteins and markers of inflammation/coagulation were between nHDLox and IL-6 (r = 0.36, P < 0.01), nHDLox and hs-CRP (r = 0.27, P < 0.001) and between nHDLox and D-dimer (r = 0.19, P < 0.01) and remained statistically significant (PFDR < 0.05) even after adjusting for FDR, age, sex, race, BMI, smoking status, baseline CD4+ cell count and viral load (Table 2). Higher nHDLox and LDLox/LDL (but not LDLox) were associated with higher levels of plasma markers of innate immune activation (sCD163 but not sCD14) and T-cell activation (sIL-2r) as well as cellular markers of T-cell activation such as expression of CD38 and HLA-DR (Supplemental Tables 1 and 2, https://links.lww.com/QAD/A975). Similar results were observed for CD4+ and CD8+ T cells. LDLox/LDL levels correlated with sCD14 levels. We also found an inverse relationship between nHDLox and CD38-DR+ T cells, the latter having previously been correlated with favorable outcome in the MACS cohort (Supplemental Table 2, https://links.lww.com/QAD/A975) . There were no relationships between levels of plasma-oxidized lipoproteins, inflammatory monocytes and cellular monocyte expression of CD163 (Supplemental Table 2, https://links.lww.com/QAD/A975). The most notable positive associations between oxidized lipoproteins and markers of immune activation at baseline were between nHDLox and CD38 expression on T cells (for both CD4+ and CD8+ T cells r = 0.34, P < 0.001) and sCD163 (r = 0.30, P < 0.001) (Fig. 2, Supplemental Figure 1, https://links.lww.com/QAD/A975); these associations remained statistically significant (PFDR < 0.05) even after adjusting for covariates (Tables 2 and 3).
Relationship between oxidized lipoproteins with markers of inflammation, coagulation and immune activation in antiretroviral therapy–treated individuals with suppressed viremia
Consistent with the data in viremic ART-naive individuals, we also found that LDLox, LDLox/LDL and nHDLox were positively associated with plasma biomarkers of inflammation at 96 weeks of effective ART (Supplemental Table 1, https://links.lww.com/QAD/A975). Most notably, nHDLox had positive associations with IL-6 (r = 0.27, P < 0.001) (Fig. 1) even after adjusting for covariates and applying the FDR correction (Table 2). The relationships of LDLox/LDL ratio and LDLox with hs-CRP and D-dimer were not consistent (Supplemental Table 1, https://links.lww.com/QAD/A975, Tables 2 and 3). We found that higher HDLox, but not LDLox or LDLox/LDL, were associated with higher levels of plasma sCD163 (r = 0.14, P = 0.05) at 96 weeks of effective ART (Supplemental Table 1, https://links.lww.com/QAD/A975) (Fig. 2) but this association did not remain significant after covariate adjustment (Table 2).
Declines in plasma levels of oxidized HDL over 96 weeks of antiretroviral therapy were associated with declines in markers of inflammation and immune activation
There were consistent positive associations between declines over 96 weeks in levels of nHDLox and IL-6, hs-CRP, sCD14, sCD163 and inflammatory monocytes (Supplemental Table 2, https://links.lww.com/QAD/A975) that remained significant after adjusting for covariates and controlling the FDR (Tables 2 and 3). During this same interval, LDLox and LDLox/LDL ratio increased but there were no consistent relationships between changes in LDLox, LDLox/LDL ratio and changes in markers of inflammation, coagulation and immune activation. In the subset of nHDLox values that declined most over time (first tertile), all significant associations were more notable and there was a largest decline in levels of IL-6 (data not shown).
Association between oxidized lipoproteins and markers of T-cell senescence and exhaustion in antiretroviral therapy–naive and in antiretroviral therapy–treated individuals with suppressed viremia
We found that higher nHDLox and LDLox/LDL (but not LDLox) were associated with higher cellular markers of T-cell senescence (% CD57+ of CD8+ T cells) and exhaustion (% PD1+ of CD4+ and CD8+ T cells) in ART-naive individuals (Supplemental Table 3, https://links.lww.com/QAD/A975). These associations were not present at 96 weeks of ART. Changes in levels of nHDLox and LDLox/LDL over 96 weeks were positively associated with changes in % CD28-CD57+ of CD4+ T cells, and % PD1+ of CD4+ T cells. LDLox/LDL ratio had differential relationships with markers of T-cell senescence and exhaustion compared with LDLox (Supplemental Table 3, https://links.lww.com/QAD/A975). All the noted relationships were weak, not consistent across all time points (baseline, week 96 and changes over 96 weeks), were attenuated and did not remain statistically significant after adjusting for covariates (Supplemental Table 4, https://links.lww.com/QAD/A975).
In this prospective study of ART-naive patients initiating RAL, ATV/r or DRV/r with TDF/FTC and successfully achieving virologic suppression, oxidized lipoproteins and primarily HDLox were associated with markers of T-cell activation, as well as plasma levels of monocyte activation, inflammation and coagulation. We chose to focus our analyses on markers such as hs-CRP, D-dimer, sCD14, sCD163 and CD38 expression that have been associated with serious clinical events in HIV-infected persons, including CVD and mortality [35,36]. To our knowledge, this is the most comprehensive prospective study describing changes in oxidized lipoproteins and immune activation (both M/M and lymphocyte) and inflammation after ART initiation and successful immune suppression. The data from this prospective study with in-vivo oxidized lipoproteins from HIV-infected patients are consistent with our prior data  and data from others  that have shown that in-vitro oxidized lipoproteins directly upregulate immune activation in vitro. Thus, we hypothesize that oxidized lipoproteins have a central role in HIV pathogenesis that both result from and contribute to systemic inflammation and immune activation of HIV infection .
Consistent with the proinflammatory effect of the oxidized lipoproteins, overall, we found positive associations of both HDLox and LDLox with various plasma biomarkers of inflammation and coagulation in both viremic and ART-treated (at 96 weeks) HIV-infected persons. HDLox showed consistent positive associations over time with IL-6 and hs-CRP, which have been associated with serious clinical events in HIV-infected persons, including CVD and mortality [35,36]. Interestingly, we found that successful ART increased rather than decreased levels of LDLox. Initiation of ART within HIV-infected patients reduces markers of systemic inflammation but there is incomplete reversal of systemic inflammation . HIV-infected individuals receiving ART may have higher oxidative stress compared with HIV-infected naive or healthy patients due to higher production of reactive oxygen species (ROS) and alterations in antioxidant systems [38,39]. Thus, ART, different levels of ROS and antioxidant systems in treated compared with ART-naive HIV-infected persons, may explain the discordant relationship between LDLox and markers of systemic inflammation before and after ART initiation.
Consistent with our hypothesis that the immunostimulatory effects of oxidized lipoproteins (that carry oxidized lipids) may contribute to HIV-related immune activation, there were consistent positive associations of both HDLox and LDLox/LDL with several markers of immune activation in ART-naive viremic persons. The immunostimulatory effects of oxidized lipoproteins have been shown in other inflammatory states . Dysfunctional HDL that is known to be oxidized [14–17], has previously been shown in vitro to directly influence monocyte  and dendritic cell  function in systemic inflammatory states [40,41]. Lipoproteins bind endotoxin that is present in viremic HIV-infected individuals, acts synergistically with LDLox and may contribute to immune activation . Thus, further studies are needed to elucidate whether oxidized lipoproteins, through effects on immunity and endotoxin, may contribute to immune activation in viremic HIV-infected individuals.
In view of our prior data that oxidized lipoproteins directly induce T-cell activation in peripheral blood mononuclear cells from HIV-infected ART-treated persons , we hypothesized that oxidized lipoproteins may contribute to immune activation in ART-treated HIV-infected individuals. Consistent with this hypothesis we found that after 96 weeks of successful ART, HDLox was associated with several biomarkers of immune activation and importantly decline in HDLox over 96 weeks was also positively associated with decline over 96 weeks in these biomarkers of immune activation even after adjustment for multiple comparisons, demographics, entry CD4+ cell count and HIV-1 RNA. More specifically, HDLox was associated with sCD163, and there were consistent positive associations between changes over 96 weeks in levels of HDLox with several markers of M/M (sCD14 and sCD163 inflammatory monocytes) and T-cell (cellular expression of CD38 and HLA-DR) activation. In a prior small study of 54 HIV-infected patients in which 91% were receiving ART, both LDL and LDLox correlated positively with sCD14 and in-vitro stimulation with LDLox, resulted in expansion of inflammatory monocytes . In a randomized trial of rosuvastatin in HIV-infected patients on ART, LDLox levels decreased 24 weeks after statin therapy was associated with changes in markers of monocyte activation and independently predicted changes in IMT, supporting our findings of the importance of oxidized lipids in potentially driving immune activation on ART . In our study, there was also a robust positive association of HDLox with sCD163, a marker of M/M activation that has been linked to CVD in HIV disease . These data are consistent with our prior data in a cohort of 102 HIV-infected treated patients, in which increased HDL redox activity, a measure of HDL function, correlated positively with sCD163 . Interestingly, the higher increases in baseline CD8+ T-cell activation in viremic patients were also seen in patients with the highest HDLox and sCD163. CD163 is shed in response to inflammation and is a scavenger receptor for complexes of hemoglobin/haptoglobin, which may alter HDL function . The exact mechanisms that may mediate the interplay between HDLox and immune activation remain to be determined.
Senescent T cells may increase the risk of morbidity, such as CVD . Modified lipoproteins have pleomorphic atherogenic effects  and may directly accelerate senescence [19,20,48] and contribute to cell exhaustion. We found weak and inconsistent relationships between HDLox and LDLox/LDL with markers of T-cell senescence and exhaustion, across all time points, which did not remain significant after covariate adjustment. Further research is needed to determine whether oxidized lipids may contribute to HIV-related T-cell dysfunction.
The differential immunoregulatory effects of HDLox versus LDLox during the first few years of ART treatment remain unknown. HDL lipids are oxidized in preference to those in LDL when human plasma is exposed to ROS . Moreover, our data corroborate prior evidence that LDLox/LDL oxidation ratio may be a better marker of in-vivo oxidation of LDL compared with total levels of LDLox. Thus, further studies to elucidate the role of oxidized lipoproteins in HIV-related pathogenesis should focus on both HDLox and LDLox as well as the ratio of oxidized lipoproteins to their total plasma levels.
Our study has several limitations. This analysis of oxidized lipoproteins was not the primary outcome of the A5260s study and may have limited power to detect complex modifications of lipoproteins that occur in vivo in the context of measuring oxidized lipoproteins in a population with an overall low CVD risk, in the setting of initiation of different ART regimens during a period in which there may be major changes in inflammation and oxidative stress that may further increase between patient variability and may compromise the ability to detect differences in measures of oxidized lipoproteins, in cryopreserved rather than fresh samples [14,17] and using biochemical assays that have limitations.
This is also recognized that although our in-vitro data suggest that in-vitro oxidized lipoproteins directly upregulate immune activation , oxidized lipoproteins may also reflect and result from  systemic inflammation and immune activation that may be driven by several other mechanisms in HIV infection. For example, ART may directly affect oxidative stress and immune activation in addition to its antiviral effects [38,50], and these effects may lead to increased plasma levels of oxidized lipoproteins.
Despite the above limitations, this is the most comprehensive prospective study describing changes in oxidized lipoproteins with regard to markers of immune activation and inflammation after ART initiation. Our data support the hypothesis that there is a cycle of HIV-induced immune activation, inflammation, production of oxidized lipoproteins that contributes to further immune activation. Further studies are needed to confirm these findings and further elucidate the differential proinflammatory role of HDLox versus LDLox in HIV infection. A deeper understanding of the specific mechanisms causing chronic immune activation is crucial to target immune activation in HIV-infected individuals.
ACTG 5260s team members: H. Hodis, C. Godfrey, B. Jarocki, A. Benns, K. Braun.
We thank the staff and patients from the following hospitals who participated in ACTG (in alphabetical order): Beth Israel Deaconess Medical Center, Brigham and Womens Hospital, Case University CRS, Duke University Medical Center, Harbor-UCLA Medical Center, Houston AIDS Research Team CRS, John Hopkins Adult AIDS CRS, Metrohealth, New Jersey Medical School, New York University HIV/AIDS CRS, Northwestern University, Rush University Medical Center ACTG, The Ohio State University, The Ponce De Leon Center CRS, UCLA Care Center, UCSF AIDS CRS, University of Cincinnati, University of Colorado, University of North Carolina AIDS CRS, University of Pittsburg CRS, University of Rochester ACTG AIDS Care, University of Southern California, University of Washington, Vanderbilt Therapeutics CRS, Washington University.
Authors’ contributions: J.S.C., J.H.S., G.A.McC., T.T.B. and T.K. were responsible for the study concept and design. N.J., X.W. and D.E. carried out the statistical analyses. T.K., N.J., J.S.C. and O.Y. drafted the manuscript. T.K., O.Y., M.P.D., J.H.S., J.S.C., G.A.McC. and T.T.B. collected the data. All coauthors participated in discussions about the design of the study, interpretation of the findings, and critically reviewed the manuscript.
Financial support: This research was supported by NIH grants HL095132, HL095126, AI068636, AI068634, AI69471, AI069501 and AI56933, NIH/NCATS Grant # UL1TR000124, NIH K08AI08272. The study received additional financial support from Gilead, Merck, Bristol Myers Squibb, Janssen. The project described was supported by Award Number UM1 AI068634, UM1 AI068636 and UM1 AI106701 from the National Institute of Allergy and Infectious Diseases. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or any of the funders.
Conflicts of interest
All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
T.T.B. has served as a consultant for BMS, GSK, Merck, Abbott, Gilead and ViiV Healthcare and has received research funding from Merck and GSK. J.S.C. has served as a consultant for Gilead and has received research funding from Merck. J.H.S. served on a Data Safety Monitoring Board for Lilly. G.A.McC. has served as consultant or received research grants from BMS, Pfizer, Gilead, ICON and GSK/ViiV. M.P.D. has served as a consultant for Gilead and Astra Zeneca, and receives research funding from Gilead, ViiV and Merck.
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