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      The Neuropeptides Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-Activating Polypeptide Control HIV-1 Infection in Macrophages Through Activation of Protein Kinases A and C

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          Abstract

          Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are highly similar neuropeptides present in several tissues, endowed with immunoregulatory functions and other systemic effects. We previously reported that both neuropeptides reduce viral production in HIV-1-infected primary macrophages, with the participation of β-chemokines and IL-10, and now we describe molecular mechanisms engaged in this activity. Macrophages exposed to VIP or PACAP before HIV-1 infection showed resistance to viral replication, comparable to that observed when the cells were treated after infection. Also, multiple treatments with a suboptimal dose of VIP or PACAP after macrophage infection resulted in a decline of virus production similar to the inhibition promoted by a single exposure to the optimal inhibitory concentration. Cellular signaling pathways involving cAMP production and activation of protein kinases A and C were critical components of the VIP and PACAP anti-HIV-1 effects. Analysis of the transcription factors and the transcriptional/cell cycle regulators showed that VIP and PACAP induced cAMP response element-binding protein activation, inhibited NF-kB, and reduced Cyclin D1 levels in HIV-1-infected cells. Remarkably, VIP and PACAP promoted G-to-A mutations in the HIV-1 provirus, matching those derived from the activity of the APOBEC family of viral restriction factors, and reduced viral infectivity. In conclusion, our findings strengthen the antiretroviral potential of VIP and PACAP and point to new therapeutic approaches to control the progression of HIV-1 infection.

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          Most cited references69

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          Hostile takeovers: viral appropriation of the NF-kappaB pathway.

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            Uncovering molecular mechanisms involved in activation of G protein-coupled receptors.

            U Gether (2000)
            G protein-coupled, seven-transmembrane segment receptors (GPCRs or 7TM receptors), with more than 1000 different members, comprise the largest superfamily of proteins in the body. Since the cloning of the first receptors more than a decade ago, extensive experimental work has uncovered multiple aspects of their function and challenged many traditional paradigms. However, it is only recently that we are beginning to gain insight into some of the most fundamental questions in the molecular function of this class of receptors. How can, for example, so many chemically diverse hormones, neurotransmitters, and other signaling molecules activate receptors believed to share a similar overall tertiary structure? What is the nature of the physical changes linking agonist binding to receptor activation and subsequent transduction of the signal to the associated G protein on the cytoplasmic side of the membrane and to other putative signaling pathways? The goal of the present review is to specifically address these questions as well as to depict the current awareness about GPCR structure-function relationships in general.
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              VPAC and PAC receptors: From ligands to function.

              Vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase activating polypeptides (PACAPs) share 68% identity at the amino acid level and belong to the secretin peptide family. Following the initial discovery of VIP almost four decades ago a substantial amount of knowledge has been presented describing the mechanisms of action, distribution and pleiotropic functions of these related peptides. It is now known that the physiological actions of these widely distributed peptides are produced through activation of three common G-protein coupled receptors (VPAC(1), VPAC(2) and PAC(1)R) which preferentially stimulate adenylate cyclase and increase intracellular cAMP, although stimulation of other intracellular messengers, including calcium and phospholipase D, has been reported. Using a range of in vitro and in vivo approaches, including cell-based functional assays, transgenic animals and rodent models of disease, VPAC/PAC receptor activation has been associated with numerous physiological processes (e.g. control of circadian rhythms) and clinical conditions (e.g. pulmonary hypertension), which underlies on-going research efforts and makes these peptides and their cognate receptors attractive targets for the pharmaceutical industry. However, despite the considerable interest in VPAC/PAC receptors and the processes which they mediate, there is still a paucity of selective and available, non-peptide ligands, which has hindered further advances in this field both at the basic research and clinical level. This review summarises the current knowledge of VIP/PACAP and the VPAC/PAC receptors with regard to their distribution, pharmacology, signalling pathways, splice variants and finally, the utility of animal models in exploring their physiological roles.
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                Author and article information

                Contributors
                URI : https://frontiersin.org/people/u/531373
                URI : https://frontiersin.org/people/u/531388
                URI : https://frontiersin.org/people/u/537786
                URI : https://frontiersin.org/people/u/571618
                URI : https://frontiersin.org/people/u/451481
                URI : https://frontiersin.org/people/u/555363
                URI : https://frontiersin.org/people/u/498389
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                12 June 2018
                2018
                : 9
                : 1336
                Affiliations
                [1] 1Laboratory on Thymus Research, Oswaldo Cruz Institute/Fiocruz , Rio de Janeiro, Brazil
                [2] 2National Institute of Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Institute/Fiocruz , Rio de Janeiro, Brazil
                [3] 3Laboratory of AIDS and Molecular Immunology, Oswaldo Cruz Institute/Fiocruz , Rio de Janeiro, Brazil
                [4] 4Laboratory of Inflammation, Oswaldo Cruz Institute/Fiocruz , Rio de Janeiro, Brazil
                Author notes

                Edited by: Aurelio Cafaro, Istituto Superiore di Sanità, Italy

                Reviewed by: Lucia Lopalco, San Raffaele Hospital (IRCCS), Italy; Jianzhong Zhu, Yangzhou University, China

                *Correspondence: Jairo R. Temerozo, jairojrt@ 123456gmail.com ; Dumith Chequer Bou-Habib, dumith@ 123456ioc.fiocruz.br , dumith.chequer@ 123456gmail.com

                Specialty section: This article was submitted to Viral Immunology, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2018.01336
                6008521
                29951068
                4dba3720-7019-43da-950b-302a5514c41d
                Copyright © 2018 Temerozo, de Azevedo, Insuela, Vieira, Ferreira, Carvalho, Bello and Bou-Habib.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 15 December 2017
                : 29 May 2018
                Page count
                Figures: 9, Tables: 1, Equations: 0, References: 80, Pages: 16, Words: 9663
                Funding
                Funded by: Conselho Nacional de Desenvolvimento Científico e Tecnológico 10.13039/501100003593
                Award ID: 308285/2013-1
                Funded by: Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro 10.13039/501100004586
                Award ID: E-26/010.001895/215
                Categories
                Immunology
                Original Research

                Immunology
                hiv-1,vasoactive intestinal peptide,pituitary adenylate cyclase-activating polypeptide,neuropeptides,macrophages,protein kinase c,protein kinase a

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