Application of a Novel CD206+ Macrophage-Specific Arterial Imaging Strategy in HIV-Infected Individuals

Zanni, Markella V.; Toribio, Mabel; Wilks, Moses Q.; Lu, Michael T.; Burdo, Tricia H.; Walker, Joshua; Autissier, Patrick; Foldyna, Borek; Stone, Lauren; Martin, Amanda; Cope, Fred O.; Abbruzzese, B.; Brady, Thomas J.; Hoffmann, Udo; Williams, Kenneth C.; El-Fakhri, Georges; Grinspoon, Steven

doi:10.1093/infdis/jix095

Cited by 35 publications

(24 citation statements)

References 14 publications

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“…Several radioligands, including those targeting inducible nitric oxide synthase (21), folate receptor-b (22,23), CD206 (24,25), and LOX-1 (26)(27)(28), have been developed to visualize macrophages, and several of these have also been used to image acute inflammation. Though present ubiquitously, TSPO expression is elevated in immunologically activated leukocytes such as microglia and macrophages (29) and has been used as a molecular target for imaging of neuroinflammation (30)(31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

Biodistribution and Radiation Dosimetry of ¹²⁴I-DPA-713, a PET Radiotracer for Macrophage-Associated Inflammation

et al. 2018

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Whole-body PET/CT was performed using I-DPA-713, a radioligand for the 18-kDa translocator protein (TSPO), to determine biodistribution and radiation dosimetry. Healthy subjects aged 18-65 y underwent whole-body PET/CT either at 4, 24, and 48 h or at 24, 48, and 72 h after intravenous injection of I-DPA-713. Time-activity curves were generated and used to calculate organ time-integrated activity coefficients for each subject. The resulting time-integrated activity coefficients provided input data for calculation of organ absorbed doses and effective dose for each subject using OLINDA. Subjects were genotyped for the polymorphism rs6971, and plasma protein binding of I-DPA-713 was measured. Three male and 3 female adults with a mean age of 40 ± 19 y were imaged. The mean administered activity and mass were 70.5 ± 5.1 MBq (range, 62.4-78.1 MBq) and 469 ± 34 ng (range, 416-520 ng), respectively. There were no adverse or clinically detectable pharmacologic effects in any of the 6 subjects. No changes in vital signs, laboratory values, or electrocardiograms were observed. I-DPA-713 cleared rapidly (4 h after injection) from the lungs, with hepatic elimination and localization to the gastrointestinal tract. The mean effective dose over the 6 subjects was 0.459 ± 0.127 mSv/MBq, with the liver being the dose-limiting organ (0.924 ± 0.501 mGy/MBq). The percentage of free radiotracer in blood was approximately 30% at 30 and 60 min after injection. I-DPA-713 clears rapidly from the lungs, with predominantly hepatic elimination, and is safe and well tolerated in healthy adults.

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Section: Discussionmentioning

confidence: 99%

Biodistribution and Radiation Dosimetry of ¹²⁴I-DPA-713, a PET Radiotracer for Macrophage-Associated Inflammation

et al. 2018

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“…We previously have described increased arterial inflammation in PWH and how this could also contribute to the increased risk of CVD among PWH [ [33] , [34] , [35] ]. Within the INTREPID trial, in turn, we previously demonstrated significant reduction with statin therapy of a systemic marker of arterial inflammation — Lp-PLA2 [ 7 ] — which has been associated with increased CVD in the general population [ 36 ] and among PWH [ 37 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

Assessing statin effects on cardiovascular pathways in HIV using a novel proteomics approach: Analysis of data from INTREPID, a randomized controlled trial

et al. 2018

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Background People with HIV (PWH) demonstrate increased cardiovascular disease (CVD), due in part to increased immune activation, inflammation, and endothelial dysfunction. Methods In a randomized trial (INTREPID), 252 HIV-infected participants with dyslipidemia and no history of coronary artery disease were randomized (1:1) to pitavastatin 4 mg vs. pravastatin 40 mg for 52 weeks. Using a proteomic discovery approach, 92 proteins biomarkers were assessed using Proximity Extension Assay technology to determine the effects of statins on key atherosclerosis and CVD pathways among PWH. 225 participants had specimens available for biomarker analysis pre- and post-baseline. Findings The mean age was 49.5 ± 8.0 (mean ± SD), LDL-C 155 ± 25 mg/dl and CD4 count 620 ± 243 cell/mm 3 . Among all participants, three proteins significantly decreased: tissue factor pathway inhibitor [TFPI; t-statistic = −6.38, FDR p-value<0.0001], paraoxonase 3 [PON3; t-statistic = −4.64, FDR p-value = 0.0003], and LDL-receptor [LDLR; t-statistic = −4.45, FDR p-value = 0.0004]; and two proteins significantly increased galectin-4 [Gal-4; t-statistic = 3.50, FDR p-value = 0.01] and insulin-like growth factor binding protein 2 [IGFBP-2; t-statistic = 3.21, FDR p-value = 0.03]. The change in TFPI was significantly different between the pitavastatin and pravastatin groups. Among all participants, change in TFPI related to the change in LDL-C ( r = 0.43, P < 0.0001) and change in Lp-PLA2 ( r = 0.29, P < 0.0001). Interpretation Using a proteomics approach, we demonstrated that statins led to a significant reduction in the levels of TFPI, PON3, and LDLR and an increase in Gal-4 and IGFBP-2, key proteins involved in coagulation, redox signaling, oxidative stress, and glucose metabolism. Pitavastatin led to a greater reduction in TFPI than pravastatin. These data highlight potential novel mechanisms of statin effects among PWH. Fund This work was supported by an investigator-initiated grant to S.K.G. from KOWA Pharmaceuticals America, Inc. and the National Institutes of Health [P30 DK040561; Nutrition Obesity Research Center at Harvard]. M.T. was support by National Institutes of Health [5KL2TR001100-05; Harvard Catalyst KL2 grant].

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“…Activated immune cells also contribute to plaque remodeling, promoting the development of high-risk morphology plaque features which predispose to atherothrombosis(8). In studies focused on MLHIV, systemic markers of monocyte activation have been related to arterial inflammation(9, 10), subclinical carotid and coronary artery atherosclerosis(11–14), and pathologically remodeled coronary atherosclerotic plaque(15, 16). Studies focused predominantly on WLHIV have revealed relationships between systemic immune markers and carotid atherosclerosis(17–19), as well as the percent of non-calcified coronary atherosclerotic plaque(6).…”

Section: Systemic Immune Activation/ Inflammation and Hiv-associated mentioning

confidence: 99%

“…Specific links between systemic immune activation markers and neurocognitive impairment have also been drawn among WLHIV, even those who are well-treated with ART and have undetectable serum viral load(36). Just as arterial inflammation and myocardial inflammation have been quantified by non-invasive imaging studies among people living with HIV (PLHIV) with CVD risk factors(9, 10, 25), neuroinflammation has also been quantified by non-invasive imaging studies among individuals with HIV and neurocognitive impairment(37). …”

Section: Systemic Immune Activation/ Inflammation and Hiv-associated mentioning

confidence: 99%

Sex Differences in Select Non-communicable HIV-Associated Comorbidities: Exploring the Role of Systemic Immune Activation/Inflammation

et al. 2017

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Purpose of the Review The goals of this review are to: 1) explore HIV-associated cardiovascular disease (CVD), neurocognitive impairment, and non-AIDS defining cancers (NADC) as heterogeneous model disease states fuelled in part by systemic immune activation/inflammation; 2) consider sex-differences in the epidemiology of these diseases in both high-resource and lower-resource settings; and 3) examine biological and environmental factors which may contribute to heightened systemic immune activation/inflammation specifically among WLHIV. Recent findings The observation that WLHIV have higher levels of systemic immune activation/inflammation than MLHIV may be relevant to sex-differences in select non-communicable HIV-associated comorbidities. Heightened systemic immune activation among WLHIV may be influenced by sex-specific responses to the virus and to immunomodulatory agents, as well as by behavioral choices/co-morbid conditions and perturbations in the hypothalamic-pituitary-gonadal axis. Summary Additional research is needed to elucidate region-specific drivers of heightened systemic immune activation/inflammation among WLHIV and to determine whether WLHIV who present with one immune-mediated HIV-associated comorbidity (e.g. cognitive impairment) may be at increased risk for another (e.g. CVD, NADC). This kind of research would facilitate improved risk prediction for non-communicable HIV-associated comorbidities among WLHIV and the development of targeted immunomodulatory prevention strategies.

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Application of a Novel CD206+ Macrophage-Specific Arterial Imaging Strategy in HIV-Infected Individuals

Abstract: NCT02542371.

Cited by 35 publications

References 14 publications

Biodistribution and Radiation Dosimetry of ¹²⁴I-DPA-713, a PET Radiotracer for Macrophage-Associated Inflammation

Biodistribution and Radiation Dosimetry of ¹²⁴I-DPA-713, a PET Radiotracer for Macrophage-Associated Inflammation

Assessing statin effects on cardiovascular pathways in HIV using a novel proteomics approach: Analysis of data from INTREPID, a randomized controlled trial

Sex Differences in Select Non-communicable HIV-Associated Comorbidities: Exploring the Role of Systemic Immune Activation/Inflammation

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Application of a Novel CD206+ Macrophage-Specific Arterial Imaging Strategy in HIV-Infected Individuals

Abstract: NCT02542371.

Cited by 35 publications

References 14 publications

Biodistribution and Radiation Dosimetry of 124I-DPA-713, a PET Radiotracer for Macrophage-Associated Inflammation

Biodistribution and Radiation Dosimetry of 124I-DPA-713, a PET Radiotracer for Macrophage-Associated Inflammation

Assessing statin effects on cardiovascular pathways in HIV using a novel proteomics approach: Analysis of data from INTREPID, a randomized controlled trial

Sex Differences in Select Non-communicable HIV-Associated Comorbidities: Exploring the Role of Systemic Immune Activation/Inflammation

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Biodistribution and Radiation Dosimetry of ¹²⁴I-DPA-713, a PET Radiotracer for Macrophage-Associated Inflammation

Biodistribution and Radiation Dosimetry of ¹²⁴I-DPA-713, a PET Radiotracer for Macrophage-Associated Inflammation