The Effects of Neurotrophins and the Neuropeptides VIP and PACAP on HIV-1 Infection: Histories with Opposite Ends

Abstract

The nerve growth factor (NGF) and other neurotrophins, and the neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) are largely present in human tissue and can exert modulatory activities on nervous, endocrine and immune system functions. NGF, VIP and PACAP receptors are expressed systemically in organisms, and thus these mediators exhibit pleiotropic natures. The human immunodeficiency virus type 1 (HIV-1), the causal agent of the acquired immunodeficiency syndrome (AIDS), infects immune cells, and its replication is modulated by a number of endogenous factors that interact with HIV-1-infected cells. NGF, VIP and PACAP can also affect HIV-1 virus particle production upon binding to their receptors on the membranes of infected cells, which triggers cell signaling pathways that modify the HIV-1 replicative cycle. These molecules exert opposite effects on HIV-1 replication, as NGF and other neurotrophins enhance and VIP and PACAP reduce viral production in HIV-1-infected human primary macrophages. The understanding of AIDS pathogenesis should consider the mechanisms by which the replication of HIV-1, a pathogen that causes chronic morbidity, is influenced by neurotrophins, VIP and PACAP, i.e. molecules that exert a broad spectrum of physiological activities on the neuroimmunoendocrine axis. In this review, we will present the main effects of these two groups of mediators on the HIV-1 replicative cycle, as well as the mechanisms that underlie their abilities to modulate HIV-1 production in infected immune cells, and discuss the possible repercussion of the cross talk between NGF and both neuropeptides on the pathogenesis of HIV-1 infection.

RME-based pharmacology: The inhibition of viral entry as therapeutic perspective in viral diseases including AIDS. Hypothesis updated and enlarged

“…Tentatively, some of them or a combination with antiretroviral therapy (ART) may possess a therapeutic value ing the keys to close the door for HIV-1 entry (62), thus being an additional state-of-the-ART in the therapy of AIDS and AIDS-related diseases, e.g. HIV-associated neurocognitive and cardiometabolic diseases (63)(64)(65)(66).…”

VIP in HIV Diarrhea: Finding Links for the “Slim Disease”

“…The initial rise in VIP secretion may be related to a beneficial microenvironment of immune resistance. VIP have been reported to reduce viral production in HIV-1-infected human primary macrophages (Souza et al, 2014 ). The exact mechanisms of transfer of HIV-1 into gut mucosal and nerve terminals is not precisely known.…”

“…The exact mechanisms of transfer of HIV-1 into gut mucosal and nerve terminals is not precisely known. Importantly, HIV-1 does not replicate in neurons and its productive infection in other cell types leads to the release of neurotoxic viral proteins, such as Tat, Nef, Vpr, and gp120 (Souza et al, 2014 ). These peptides may cause neuronal apoptosis.…”

“…VIP exerts anti-inflammatory activity by inhibiting the activity or production of the interleukins IL-12, IL-6, IL-1β, tumor necrosis factor (TNF-α) and macrophage migration inhibitory factor, and stimulate the production of anti-inflammatory factors like IL-4 and IL-10. VIP and PACAP also participate in Th2 cell differentiation and inhibit synthesis of the Th1 cytokines IFN-γ and IL-2 (Souza et al, 2014 ). Additionally, VIP induces tolerance development in dendritic cells, induces the differentiation of T regulatory cells (T regs ) and reduces TLR2 and TLR4 expression on CD4+T cells (Chorny et al, 2006 ; Delgado and Ganea, 2013 ).…”

“…These initial suggestive hypothesis came during exploration of possible mechanisms of neurocognitive complications that arose in the HIV infected populations (before the era of HAART) (Ngwainmbi et al, 2014 ). It has been proposed that VIP could block HIV-1 entry into target cells through direct interaction with the CD4 molecule (Souza et al, 2014 ). VIP also could act as a blocking peptide by binding to gp120, and prevent HIV binding to target cells.…”