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

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.

VIP plasma levels associate with survival in severe COVID-19 patients, correlating with protective effects in SARS-CoV-2-infected cells

“…Our findings showing that VIP and PACAP inhibited the SARS-CoV-2induced activation of the subunit p65 of the transcription factor NF-kB, which is a classical inducer of inflammatory mediators 36 , pertain to a complex molecular mechanism probably participating in the neuropeptide-mediated reduction of proinflammatory cytokines by SARS-CoV-2-infected monocytes. As we also previously described for HIV-1 infection in macrophages 14 , the ability of VIP and PACAP to prevent the SARS-CoV-2-mediated NF-kBp65 activation might be associated to a concomitant neuropeptide-induced CREB activation. In fact, we detected here that the transcription factor CREB, which can act as a negative regulator of NF-kB 45,46 , is down-regulated in SARS-CoV-2-infected monocytes, in opposition to NF-kB activation in the same cells.…”

“…Given that monocytes and epithelial cells can be in close proximity in the lungs, and, thus, can interact and exchange molecules, we investigated whether Based on the fact that the transcription factor NF-kB is critically involved in the cellular production of inflammatory mediators 36 , and on our own findings that VIP and PACAP can inhibit its activation in HIV-1-infected macrophages 14 , we investigated whether both neuropeptides would exert this same activity in SARS-CoV-2-infected monocytes. As can be seen in Fig.…”

“…Taking VIP and PACAP are expressed in the central and peripheral nervous system and in many other sites, including the lymphoid tissue [17][18][19] and the lungs 15,42 , where, together with brain and gut, the higher levels of VIP are found 15,42 . Both neuropeptides regulate the inflammatory response due to their ability to decrease the production of proinflammatory mediators, such as and, specifically for viral infections, we reported that VIP and PACAP inhibit HIV-1 replication in human primary macrophages 13,14 .…”

“…Given that SARS-CoV-2 infection may trigger an uncontrolled and damaging inflammatory reaction, which might favor the virus propagation, it is critical to identify agents able to prevent the infection and concurrently thwart the prototypical excessive inflammatory reaction and tissue lesions secondary to SARS-CoV-2 infection. In this work, we evaluated whether the neuropeptides Vasoactive Intestinal Peptide (VIP) and Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP), which present immunoregulatory functions 12 and are also able to reduce viral production in HIV-1-infected macrophages 13,14 , can present the antiviral and anti-inflammatory activities needed to attenuate the damages caused by SARS-CoV-2 infection.…”

Imperative role of particulate matter in innate immunity during RNA virus infection

“…We validated RNA sequencing results for four of the top hits genes namely VIPR1 (vasoactive intestinal peptide 1), CYP1A1 (cytochrome P450, family 1, subfamily A memeber1 also known as aryl hydrocarbon hydroxylase), ALDH1A3 (aldehyde dehydrogenase 1, family member 3A) and PPP1R14A (protein phosphatase 1 regulatory inhibitor subunit 14A) using quantitative qRT-PCR analysis. These selected genes are, VIPR1, mainly located on plasma membrane and PPP1R14A majorly located on nucleus and cytoskeleton were moderately found to be involved in virus infections like HIV-1 and influenza as reported by an in-vitro study and an in-silico phosphoproteomics study in human macrophages respectively [51-53]. CYP1A1 was recently reported to be involved in many virus infections especially hepatitis B and hepatitis C virus [54-56].…”