15
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Reduction of soluble CD163, substance P, programmed death 1 and inflammatory markers: phase 1B trial of aprepitant in HIV-1-infected adults

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Objective:

          We evaluated safety, antiviral, immunomodulatory and anti-inflammatory properties of aprepitant – a neurokinin 1 receptor antagonist.

          Design:

          Phase IB randomized, placebo-controlled, double-blinded study.

          Methods:

          Eighteen patients were randomized (nine to aprepitant and nine to placebo). The patients received once-daily treatment (375 mg aprepitant or placebo by oral administration) for 2 weeks and were followed off drug for 4 weeks.

          Results:

          There were no significant changes in the plasma viremia or CD4 + T cells during the dosing period. Aprepitant treatment was associated with significant decreases of median within patient change in percentages of CD4 + T cells expressing programmed death 1 (−4.8%; P = 0.04), plasma substance P (−34.0 pg/ml; P = 0.05) and soluble CD163 (−563 ng/ml; P = 0.02), with no significant changes in the placebo arm. Mean peak aprepitant plasma concentration on day 14 was 7.6 ± 3.1 μg/ml. The use of aprepitant was associated with moderate increases in total cholesterol, low-density lipoprotein and high-density lipoprotein (median change = +31 mg/dl, P = 0.01; +26 mg/dl, P = 0.02; +3 mg/dl, P = 0.02, respectively).

          Conclusion:

          Aprepitant was safe and well tolerated. At the dose used in this proof-of-concept phase IB study, aprepitant did not show a significant antiviral activity. Aprepitant-treated patients had decreased numbers of CD4 + programmed death 1-positive cells and decreased plasma levels of substance P and soluble CD163, suggesting that blockade of the neurokinin 1 receptor pathway has a role in modulating monocyte activation in HIV infection. Prospective studies in virologically-suppressed individuals are warranted to evaluate the immunomodulatory properties of aprepitant. Exposures exceeding those attained in this trial are more likely to elicit clinical benefit.

          Related collections

          Most cited references 43

          • Record: found
          • Abstract: found
          • Article: not found

          The PD-1-PD-L pathway in immunological tolerance.

          Since the first observation of spontaneous autoimmune diseases in programmed cell death 1 (PD-1) knockout mice, PD-1 has been postulated to have essential roles in the regulation of autoimmunity but the precise mechanism was largely unknown. Recent studies clearly demonstrated that PD-1 has dual roles in immunological tolerance: induction and maintenance of peripheral tolerance. PD-1 ligands (PD-Ls) on antigen-presenting cells have been shown to switch off autoreactive T cells and induce peripheral tolerance, whereas those on parenchymal cells prevent tissue destruction by suppressing effector T cells to maintain tolerance. In addition, PD-1 and other immuno-inhibitory receptors have been shown to collaborate in the regulation of tolerance. Here, we review recent studies on the role of PD-1 in immunological tolerance and discuss possible clinical applications of PD-1 manipulation.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Redefining the viral reservoirs that prevent HIV-1 eradication.

            This Perspective proposes definitions for key terms in the field of HIV-1 latency and eradication. In the context of eradication, a reservoir is a cell type that allows persistence of replication-competent HIV-1 on a timescale of years in patients on optimal antiretroviral therapy. Reservoirs act as a barrier to eradication in the patient population in which cure attempts will likely be made. Halting viral replication is essential to eradication, and definitions and criteria for assessing whether this goal has been achieved are proposed. The cell types that may serve as reservoirs for HIV-1 are discussed. Currently, only latently infected resting CD4(+) T cells fit the proposed definition of a reservoir, and more evidence is necessary to demonstrate that other cell types, including hematopoietic stem cells and macrophages, fit this definition. Further research is urgently required on potential reservoirs in the gut-associated lymphoid tissue and the central nervous system. Copyright © 2012 Elsevier Inc. All rights reserved.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Soluble CD163.

               J Möller (2012)
              CD163 is an endocytic receptor for haptoglobin-hemoglobin complexes and is expressed solely on macrophages and monocytes. As a result of ectodomain shedding, the extracellular portion of CD163 circulates in blood as a soluble protein (sCD163) at 0.7-3.9 mg/l in healthy individuals. The function of sCD163 is unknown, but during inflammation and macrophage activation, sCD163 levels increase acutely due to metalloproteinase-mediated cleavage near the cell membrane. It is now evident that sCD163 is very useful as a biomarker of macrophage activation in various inflammatory diseases, such as macrophage activation syndrome, sepsis, and liver disease. Moreover, sCD163 is a general risk marker of comorbidity and mortality in several chronic inflammatory disease states. Recently, sCD163 has been shown to be strongly associated with later development of type 2 diabetes in both lean and obese subjects, likely due to macrophage infiltration of adipose tissue and the liver. This review summarizes the current knowledge on the regulation of sCD163 in normal and pathological states and also deals with analytical aspects of sCD163 measurements in biological samples.
                Bookmark

                Author and article information

                Journal
                AIDS
                AIDS
                AIDS
                AIDS (London, England)
                Lippincott Williams & Wilkins
                0269-9370
                1473-5571
                15 May 2015
                06 May 2015
                : 29
                : 8
                : 931-939
                Affiliations
                [a ]Department of Medicine
                [b ]Department of Pediatrics
                [c ]Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania
                [d ]The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania
                [e ]Westat, Rockville, Maryland, USA.
                Author notes
                Correspondence to Steven D. Douglas, MD, Professor and Associate Chair, Department of Pediatrics, Perelman School of Medicine, Division of Allergy-Immunology, Children's Hospital of Philadelphia, Abramson Building Room 1208A, Philadelphia, PA 19104, USA. Tel: +1 215 590 3561; e-mail: douglas@ 123456email.chop.edu
                Article
                10.1097/QAD.0000000000000638
                4472318
                Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0

                Product
                Categories
                Clinical Science
                Custom metadata
                TRUE

                Comments

                Comment on this article