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Plasma Soluble CD163 Level Independently Predicts
All-Cause Mortality in HIV-1-Infected Individuals
 
 
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Download PDF here
 
"It is now well appreciated that human immunodeficiency virus (HIV)-infected individuals in the modern treatment era have an increased risk of morbidity and mortality, compared with the general population, particularly among those who initiate antiretroviral therapy (ART) at advanced disease stages. Immune activation and inflammation persist despite suppressive ART and are thought to drive many of these complications."
 
"In conclusion, our study showed that sCD163 predicted all-cause mortality in ART recipients, suggesting the importance of monocyte/macrophage activation and a possible target for intervention. Further, our demonstration of a strong risk gradient in the highest quartile of patients suggests that elevated plasma sCD163 levels may help identifying a risk group requiring further work-up and surveillance.
 
.....Our findings indicate that sCD163 levels in combination with patient characteristics may be used to identify individuals at risk of disease and death.
 
Other inflammatory biomarkers have been linked to an increased risk of HIV-related all-cause mortality. Interestingly, the strongest associations with mortality were seen in untreated individuals for interleukin 6, D-dimer, and sCD14 levels and to a lesser extent in treated individuals [6, 7]. Plasma sCD163 levels, in contrast, were predictive of mortality in treated but not untreated individuals, indicating that sCD163 levels could be useful to identify individuals with ongoing inflammation despite successful ART.
 
During untreated HIV infection, inflammation and activation is driven by HIV replication. In individuals receiving ART, low-level HIV replication, microbial translocation, viral coinfections (eg, cytomegalovirus or HCV infection), comorbidities, and lifestyle factors, such as tobacco and alcohol use, are believed to contribute to chronic inflammation [36]. Beltran et al showed that coinfection with HCV and ongoing HIV replication was associated with an attenuated decrease in plasma sCD163 levels after initiation of ART....HCV status is likely a marker of other unfavorable risks, such as injection drug use.
 
Future studies should investigate a possible association between elevated sCD163 levels and diseases characterized by chronic inflammation, such as cardiovascular disease, diabetes, and cancer. The causes of death varied and included infection, cancer, cardiovascular, respiratory, hepatic, and alimentary tract diseases. Our analysis did not indicate differences in risk of death caused by infectious disease, noninfectious disease, or cardiovascular disease."
 
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Editors Choice: Plasma Soluble CD163 Level Independently Predicts All-Cause Mortality in HIV-1-Infected Individuals
 
Abstract
 
Background.
CD163, a monocyte- and macrophage-specific scavenger receptor, is shed as soluble CD163 (sCD163) during the proinflammatory response. Here, we assessed the association between plasma sCD163 levels and progression to AIDS and all-cause mortality among individuals infected with human immunodeficiency virus type 1 (HIV).
 
Methods. Plasma sCD163 levels were measured in 933 HIV-infected individuals. Hazard ratios (HRs) with 95% confidence intervals (CIs) associated with mortality were computed by Cox proportional hazards regression.
 
Results. At baseline, 86% were receiving antiretroviral treatment, 73% had plasma a HIV RNA level of <50 copies/mL, and the median CD4+ T-cell count was 503 cells/µL. During 10.5 years of follow-up, 167 (17.9%) died. Plasma sCD163 levels were higher in nonsurvivors than in survivors (4.92 mg/L [interquartile range {IQR}, 3.29-8.65 mg/L] vs 3.16 mg/L [IQR, 2.16-4.64 mg/L]; P = .0001). The cumulative incidence of death increased with increasing plasma sCD163 levels, corresponding to a 6% or 35% increased risk of death for each milligram per liter or quartile increase, respectively, in baseline plasma sCD163 level (adjusted HR, 1.06 [95% CI, 1.03-1.09] and 1.35 [95% CI, 1.13-1.63], respectively).
 
Conclusions. Plasma sCD163 was an independent marker of all-cause mortality in a cohort of HIV-infected individuals, suggesting that monocyte/macrophage activation may play a role in HIV pathogenesis and be a target of intervention.
 
see below following Editorial
 
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Editorial Commentary
 
Soluble CD163 and Clinical Outcomes in Treated HIV Infection: Insights into Mechanisms
 
Journal of Infectious Diseases Advance Access published July 26, 2016
 
Peter W. Hunt
Department of Medicine, University of California-San Francisco
 
It is now well appreciated that human immunodeficiency virus (HIV)-infected individuals in the modern treatment era have an increased risk of morbidity and mortality, compared with the general population, particularly among those who initiate antiretroviral therapy (ART) at advanced disease stages. Immune activation and inflammation persist despite suppressive ART and are thought to drive many of these complications. Nevertheless, there has continued to be uncertainty as to the most appropriate immunologic targets for therapeutic interventions. A key step in this process is demonstrating that biomarkers of a candidate interventional target predict subsequent clinical events in observational studies. Over the last few years, several studies in treated HIV-infected individuals have demonstrated that plasma markers of innate immune activation and inflammation tend to predict non-AIDS-defining morbidity and mortality more strongly than cellular markers of T-cell activation [1-3]. Yet, the specific cellular sources of those inflammatory mediators have been unclear. This is, in part, because most studies that are large enough to measure relatively uncommon clinical outcomes are typically too large to afford banking viably cryopreserved leukocytes from all participants. Thus, studies linking monocyte phenotypes to end-organ disease in treated HIV infection have largely been limited to surrogate markers of disease (eg, coronary artery calcium scores [4]), instead of clinical events. Additionally, the phenotype and function of innate immune cells in circulation (eg, monocytes) may not reflect the status of their more numerous counterparts (eg, macrophages) in tissues, which may also contribute to soluble inflammatory mediators in plasma. Despite these limitations, several studies have highlighted the potential importance of monocyte and macrophage activation in predicting end-organ disease in treated HIV infection by assessing soluble receptors (eg, soluble CD14 [sCD14]) that are often shed by activated monocytes and macrophages in response to lipopolysaccharide and other stimuli [1, 2, 5]. Nevertheless, there is continued uncertainty as to whether sCD14 levels are specific markers of monocyte and macrophage activation, since it is shed not just by monocytes and macrophages, but also by other cell types, including neutrophils and even hepatocytes, in response to inflammatory stimuli [6].
 
In their cohort study in this issue of The Journal of Infectious Diseases [7], Knudsen et al present the first data linking plasma levels of the monocyte/macrophage activation marker soluble CD163 (sCD163) to clinical outcomes in treated HIV infection. In a sample of 933 HIV-infected individuals in Denmark whose viral loads were largely suppressed by ART, they found that each quartile increase in plasma sCD163 level was significantly associated with a 35% increased risk of death. Unlike sCD14, sCD163 is relatively specific for monocyte/macrophage activation. Thus, this study provides the most compelling data to date linking monocyte and macrophage activation to clinical end points in treated HIV infection. While this relationship appeared slightly stronger for cardiovascular causes of death (as might have been predicted, based on earlier studies linking sCD163 to vascular inflammation [8]), a similar relationship was also observed with other noninfectious and infectious causes of death, potentially suggesting a role of monocyte and macrophage activation in contributing to multiple end-organ diseases in this setting. Interestingly, in another recent cohort study of HIV-infected individuals whose viral loads were largely suppressed by ART, conducted in the United States, higher plasma sCD163 levels were also linked to T-cell activation and expansion of poorly differentiated effector CD8+ T cells [9], a defect that also appears to predict mortality in treated HIV infection [10]. Whether monocyte and macrophage activation is a cause or consequence of adaptive immune defects in treated HIV infection (or confounded by some other related immunologic pathway) remains to be seen. Nevertheless, these prior observations linking sCD163 levels to adaptive immune defects in treated HIV infection provide a potential mechanistic link to the increased infection-related mortality seen in the current study by Knudsen et al.
 
A great strength of the study by Knudsen et al is its large sample size and linkage to the robust population-based Danish cohort study, which enabled the investigators to link sCD163 to not just clinical outcomes, but also a wide variety of potentially confounding clinical covariates and health-related behaviors. Indeed, many health-related behaviors are known to increase immune activation, including smoking and injection drug use. Since HIV-infected individuals are more likely to smoke and use injection drugs than the general population, some have argued that the increase in immune activation observed in treated HIV infection-and the relationship between immune activation and adverse clinical outcomes in this setting-might be largely or, at least in part, due to enrichment for these health-related behaviors. The study by Knudsen et al provides some important evidence to the contrary. Indeed, the relationships between sCD163 levels and mortality in this study were significantly stronger among nonsmokers than among smokers and stronger among non-injection drug users than among injection drug users, suggesting that smoking- and injection drug use-related increases in sCD163 levels were not likely to be driving the significant mortality associations observed.
 
Other interactions described by Knudsen et al are similarly enlightening with regard to (1) the mechanistic pathways linking monocyte and macrophage activation to mortality and (2) the subgroups of individuals most likely to benefit from interventions to reduce monocyte and macrophage activation. For example, women had greater sCD163 levels than men, reminiscent of the heightened responses of premenopausal women to Toll-like receptor ligands, reported in earlier studies [11]. Furthermore, the relationship between sCD163 levels and mortality was somewhat stronger in women than in men, suggesting not just that these sex-based differences in immune activation may be clinically relevant, but also that HIV-infected women may stand to derive even greater benefit from interventions to reduce monocyte and macrophage activation than HIV-infected men. Higher levels of HIV replication were also strongly associated with sCD163 levels in this study. Nevertheless, higher sCD163 levels predicted mortality much more strongly among individuals with ART-suppressed viral loads than among viremic individuals, suggesting that the mortality associations with sCD163 are not simply driven by untreated viral replication and/or poor adherence to ART and that the population with ART suppression may well stand to benefit from interventions to reduce immune activation.
 
While the report by Knudsen et al is a major step forward in understanding the relationships between monocyte and macrophage activation and clinical outcomes in treated HIV infection, many unanswered questions remain. For example, since other biomarkers were not measured in this study, it is impossible to know whether sCD163 (or the monocyte/macrophage activation it represents) is causally associated with mortality or simply a marker for some other closely related inflammatory pathway that may be even more strongly predictive of and causally associated with mortality. Furthermore, the root drivers of the persistent elevations in sCD163 levels observed remain unclear. While continued HIV expression by infected cells in tissues, coinfections, including cytomegalovirus, and microbial translocation have all been implicated as potential drivers of the persistent inflammatory state in this setting [12], the most optimal targets for interventions remain unclear. It also remains unclear whether the contributions of each of these drivers to persistent immune activation will be evident even in those who initiate ART very early in the course of the infection and/or at high nadir CD4+ T-cell counts. Nevertheless, ameliorating the harmful effects of immune activation during treated HIV infection may be like cutting down a tree. One could try to cut away each individual "root" driver, and one could also try pruning each individual "branch" (representing the many parallel inflammatory pathways that contribute to morbidity and mortality). Alternatively, one could cut the tree at the trunk, a common immunologic pathway that is fed by all the major roots and that gives rise to most of the parallel inflammatory pathways leading to disease. Perhaps monocyte and macrophage activation could be the tree trunk in treated HIV infection. Targeted interventions directed at monocyte and macrophage activation may well help answer this question in the future.
 
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Editors Choice: Plasma Soluble CD163 Level Independently Predicts All-Cause Mortality in HIV-1-Infected Individuals
 
Abstract
 
Background
CD163, a monocyte- and macrophage-specific scavenger receptor, is shed as soluble CD163 (sCD163) during the proinflammatory response. Here, we assessed the association between plasma sCD163 levels and progression to AIDS and all-cause mortality among individuals infected with human immunodeficiency virus type 1 (HIV).
 
Methods Plasma sCD163 levels were measured in 933 HIV-infected individuals. Hazard ratios (HRs) with 95% confidence intervals (CIs) associated with mortality were computed by Cox proportional hazards regression.
 
Results At baseline, 86% were receiving antiretroviral treatment, 73% had plasma a HIV RNA level of <50 copies/mL, and the median CD4+ T-cell count was 503 cells/µL. During 10.5 years of follow-up, 167 (17.9%) died. Plasma sCD163 levels were higher in nonsurvivors than in survivors (4.92 mg/L [interquartile range {IQR}, 3.29-8.65 mg/L] vs 3.16 mg/L [IQR, 2.16-4.64 mg/L]; P = .0001). The cumulative incidence of death increased with increasing plasma sCD163 levels, corresponding to a 6% or 35% increased risk of death for each milligram per liter or quartile increase, respectively, in baseline plasma sCD163 level (adjusted HR, 1.06 [95% CI, 1.03-1.09] and 1.35 [95% CI, 1.13-1.63], respectively).
 
Conclusions.Plasma sCD163 was an independent marker of all-cause mortality in a cohort of HIV-infected individuals, suggesting that monocyte/macrophage activation may play a role in HIV pathogenesis and be a target of intervention.
 
Immune activation and chronic inflammation is associated with disease progression in human immunodeficiency virus (HIV) infection. Although inflammation and immune activation are most profound during untreated HIV infection, virtually all components of innate and adaptive immunity remain dysfunctional despite antiretroviral treatment (ART). Consequently, many individuals experience persistent abnormalities involving immune activation, inflammation, and coagulation [1, 2]. T-cell activation rapidly declines following initiation of antiretroviral therapy (ART), but changes in innate immune activation markers are more variable [3-5]. Selected markers of inflammation and coagulation have been correlated to HIV-associated outcomes [6-9].
 
CD163 is a haptoglobin-hemoglobin scavenger receptor expressed predominantly on monocytes and macrophages [10]. CD163 is reported to be involved in erythroblast adhesion [11], immune sensing of bacteria [12], and binding of the cytokine TWEAK [13]. Upon exposure to proinflammatory stimuli such as Toll-like receptor activation by lipopolysaccharide or other microbial ligands, soluble CD163 (sCD163) is shed from monocytes by proteinase-mediated cleavage during the inflammatory response [14]. The cleavage is mediated by ADAM-17, an inflammation-inducible enzyme that also leads to release of tumor necrosis factor α (TNF-α); hence the alternative designation of ADAM17 as TNF-α-activating enzyme [15, 16].
 
The function of sCD163 is hitherto unknown, but it is believed to be important in resolution of inflammation [17]. sCD163 has been associated with disease progression in viral hepatitis [18] and with increased mortality following sepsis and tuberculosis [19, 20].
 
Recent studies have shown that levels of sCD163 are elevated in HIV-infected individuals and that sCD163 plasma levels remain elevated despite ART, suggesting residual monocyte/macrophage activation after HIV suppression [21-25]. Coinfection with hepatitis C virus (HCV), ongoing HIV replication, and treatment with a protease inhibitor were associated with an attenuated decrease in plasma sCD163 level in ART recipients [23]. Further, elevated plasma sCD163 levels have been associated with coronary lesions and stenosis in HIV-infected individuals receiving ART [21, 24, 26]. Collectively, these studies indicate that plasma sCD163 levels are correlated with HIV-related morbidity. However, a role for sCD163 in disease progression and outcome has not been determined. The objective of this study is to evaluate the influence of plasma sCD163 levels on progression to death and AIDS in a contemporary cohort of HIV-infected individuals who were followed for >10 years.
 
There was a positive correlation between plasma sCD163 levels and plasma HIV RNA loads for all patients (r = 0.40, P = .0001) and for the subgroup of patients with detectable plasma HIV RNA loads (>50 copies/mL; r = 0.36, P = .0001). There was an inverse correlation between plasma sCD163 levels and blood CD4+ T-cell counts (r = -0.25, P = .0001) for all patients and for patients with detectable HIV RNA loads (r = -0.20, P = .0001). The underlying cause of death had been determined for 144 cases (86.2%). Infection was the most common cause of death (n = 54), followed by cancer (n = 25), respiratory or cardiovascular disease (n = 17), and alimentary tract disease (n = 7). Unintentional injury or suicide (n = 17) and other or unknown causes (n = 14) accounted for the remaining deaths.
 
 
 
 
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