Immune Activation and Inflammation in People With Human Immunodeficiency Virus: Challenging Targets
Year: 2019
Type: article
Abstract: (See the Major Article by Macatangay et al., on pages 1598–606.) People with human immunodeficiency virus (HIV) (PWH) remain at increased risk of cardiovascular, hepatic, renal, neurocognitive, and other end-organ diseases despite suppressive antiretroviral therapy (ART) [1–3]. Specifically, rates of cardiovascular disease are 1.5–2 times higher in the setting of HIV compared with the general population [4]. Markers of systemic inflammation, such as soluble CD14 (sCD14), soluble CD163 (sCD163), interleukin 6 (IL-6), and soluble TNF receptor II, are consistent predictors of increased morbidity and mortality rates in PWH, suggesting that systemic inflammation may be on the causative pathway for these comorbid conditions [5–8]. Excess T-cell activation based on CD38 and HLA-DR expression has been associated with poor CD4+ T-cell recovery and increased mortality rates [9–11]. In the modern ART era, however, T-cell activation is associated with mortality in resource-limited settings but not in resource-rich settings [8, 12]. Many ongoing initiatives are focused on identifying the key mechanisms underlying the excess morbidity in the setting of HIV infection. Several factors have been identified as potential drivers of increased immune activation and inflammation, including increased microbial translocation across a permeable gut barrier [13]; coinfections, such as cytomegalovirus [14]; residual HIV [15]; and lifestyle factors, such as cigarette smoking [16]. How these factors confer excess risk for non-AIDS diseases remains an area of intense research. One potential mechanism contributing to these end-organ diseases is adenosine metabolism. In the setting of vascular inflammation and stress, compensatory immunoregulatory mechanisms are activated, including adenosine production [17]. Extracellular adenosine levels are markedly increased in the setting of ischemia or inflammation and serve to facilitate relaxation of vascular smooth muscle and decrease immune activation. Adenosine decreases proinflammatory cytokine production by macrophages, suppresses CD4+ and CD8+ T-cell effector function, stimulates regulatory T-cell differentiation and activity, and decreases neutrophil adhesion and activation [18, 19]. In the setting of HIV infection, adenosine metabolism is impaired owing to decreased T-lymphocyte expression of CD73, a key enzyme in adenosine metabolism [20]. Furthermore, CD73 expression is inversely correlated with CD4+ and CD8+ T-cell activation and C-reactive protein levels [21, 22], suggesting that decreased adenosine may contribute to increased immune activation in PWH and have negative consequences for comorbid conditions of interest. Dipyridamole inhibits uptake of adenosine into multiple cell types, resulting in increased extracellular adenosine levels. In this issue of The Journal of Infectious Diseases, Macatangay and colleagues [23] conducted a placebo-controlled, 2-arm, partial cross-over, pilot study of dipyridamole given to 35 PWH receiving suppressive ART to determine whether this intervention would improve endothelial function and reduce markers of inflammation and immune activation. After 12 weeks of dipyridamole, CD8+ T-cell activation significantly decreased, with a decrease in sCD163 levels that did not reach statistical significance. In a pooled analysis, which included the dipyridamole arm (baseline to 12 weeks) and the placebo arm after crossover to dipyridamole (12–24 weeks), the decrease in CD8+ T-cell activation was no longer statistically significant (P = .058), but the authors reported a significant decrease in CD4+ T-cell activation (P = .006). Dipyridamole had no effect on endothelial function as assessed by flow-mediated dilation of the brachial artery. This study population was notably healthy, with median CD4+ T-cell counts of 724/μL in the dipyridamole and 649/μL in the placebo arm and CD4+/CD8+ T-cell ratios of 1.08 and 0.80, respectively. The baseline frequencies of activated CD4+ (2.35% and 3.13%, respectively) and CD8+ (5.95% and 4.45%, respectively) T cells were also lower than levels reported in other studies, with CD4+ and CD8+ T-cell activation being half the values reported elsewhere [24, 11]. The soluble marker levels also tended to be lower than those associated with end-organ disease and events [5–7, 25]. The relatively intact immune function of the study population may have compromised the ability to observe larger and/or significant changes in the parameters measured. Indeed, the frequency of CD73+ CD8+ T cells correlates directly with CD4+ T-cell counts in PWH [22], suggesting that those with lower CD4+ T-cell counts may be more likely to benefit. Given that, it is all the more remarkable that significant decreases in T-cell activation were observed. Other studies have aimed to attenuate inflammation and immune activation in PWH, targeting various drivers of inflammation. For example, valganciclovir, which inhibits cytomegalovirus replication, decreased CD8+ T-cell activation in immunologic nonresponders (INRs) [24]. Several studies have targeted microbial translocation. Sevelamer, a phosphate binder that decreased microbial translocation in patients receiving dialysis, showed no impact on sCD14, IL-6, or T-cell activation in PWH not taking ART [26]. Rifaximin, a luminal antibiotic, attenuated an increase in T-cell activation with no effect on sCD14 levels in a study of INRs [27], and mesalamine, the mucosal anti-inflammatory agent, had no effect on sCD14, IL-6, or T-cell activation [28]. In contrast, serum bovine immunoglobulin decreased IL-6 levels in PWH taking ART, most notably in those with the lowest CD4+ T-cell counts [29]. Pre- and probiotic studies have yielded conflicting results on T-cell activation and inflammatory markers, but most have been small pilot studies [30]. Studies targeting inflammation directly, rather than drivers of inflammation, have also yielded mixed results. Aspirin did not decrease sCD14, sCD163, IL-6, or T-cell activation in PWH taking ART [31], whereas the COX-2 inhibitor etoricoxib decreased T-cell activation but only in ART-naive PWH [32]. Hydroxychloroquine decreased T-cell activation in INRs [33], whereas chloroquine decreased T-cell activation in PWH taking ART [34] but not in INRs [35]. Prednisone also decreased T-cell activation in people with advanced HIV infection, most of whom were taking ART [36], whereas prednisolone decreased sCD14 and CD8+ T-cell activation in PWH not taking ART [37]. Blocking interleukin 1β with canakinumab decreased IL-6 levels but not T-cell activation in a small pilot study of PWH taking suppressive ART [38]. Statin studies have yielded conflicting results. Atorvastatin did not decrease T-cell activation or inflammatory markers in a mostly immunologically reconstituted population [39], whereas it did decrease CD4+ and CD8+ T-cell activation in INRs in Uganda [40] and in PWH not taking ART [41]. Rosuvastatin, in contrast, decreased sCD14 levels and CD4+ and CD8+ T-cell activation in immunologically reconstituted PWH taking ART who had either elevated T-cell activation or C-reactive protein levels [42], and pitavastatin decreased sCD14 levels in PWH taking ART with dyslipidemia [43]. The REPRIEVE trial will elucidate the effects of pitavastatin on inflammatory markers in the 800-person mechanistic substudy of the 7500-person cardiovascular end point study (NCT02344290). To generalize, targeting T-cell activation and inflammation in PWH is challenging, and the best end points to target remain unknown. The small but significant decrease in T-cell activation with dipyridamole suggests that altered adenosine metabolism and/or signaling may contribute to T-cell activation in PWH. The lack of significant effect on markers of inflammation and on endothelial function suggests that (1) decreased adenosine signaling does not play a major role in monocyte and macrophage activation in people with treated HIV infection and immune reconstitution; (2) the increase in adenosine signaling was insufficient to affect monocytes and macrophages; (3) there are compensatory mechanisms that limit the effect of targeting extracellular adenosine levels alone; or, alternatively, (4) the degree of monocyte/macrophage activation was too low at baseline to enable detection of a meaningful decrease. It is unknown whether dipyridamole would have a more profound impact in PWH with more immune activation and inflammation, such as INRs or people with higher baseline inflammatory markers. The study by Macatangay et al also highlights a significant issue with many recent clinical trials in the setting of treated HIV infection: enrolling the study population most likely to benefit. Avoiding a population with severe immune impairment to prevent toxicity or infectious adverse events must be balanced with avoiding a population that is too immunologically healthy to see an effect of the intervention under evaluation. Because we lack good surrogate markers or predictors of end-organ disease in the setting of HIV, we often fail to select a population in whom we can measure a clinically meaningful benefit from an intervention. If selecting biomarkers of inflammation and/or immune activation as end points for studies targeting the mechanisms driving end-organ disease, we need to identify participants who have heightened levels of inflammation and/or immune activation. Financial support. This work was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (grants UM1 AI068634, UM1 AI068636, UM1 AI106701, UM1AI069503, and UM1AI069452) and by the University of Alabama at Birmingham Center For AIDS Research (grant P30 AI027767-31). Potential conflicts of interest. Both authors: No reported conflicts. The 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.
Authors: Netanya S Utay, Edgar T Overton
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: G4426040137, Terry Beirn CPCRA Clinical Trials Unit, Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections, AIDS Clinical Trial Group Laboratory Center, Statistical and Data Management Center (SDMC), Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG), A-Z Clinical Trials Unit, UAB Center for AIDS Research (CFAR)
OpenAlex ID: W2959947942