neuropeptide-y and HIV-Infections

Neuropeptide Y (NPY) is one of the most abundant and phylogenetically best conserved peptides in the mammalian central and peripheral nervous system where it plays an important role in the regulation of cardiovascular, metabolic, endocrine, immunological and cognitive functions. In a prospective study we determined neuropeptide Y-like immunoreactivity (NPY-LI) in cerebrospinal fluid (CSF) and plasma of 95 HIV-seropositive (n = 49) or seronegative (n = 46) patients who underwent diagnostic CSF examination. CSF and plasma NPY-LI but not noradrenaline concentrations were higher in seropositive than in seronegative patients indicating that raised levels of NPY-LI did not result from a non-specific activation of the sympathetic nervous system. Increased CSF NPY-LI was positively correlated with the degree of HIV encephalopathy (P < 0.01, Kruskal-Wallis test). Inflammatory disorders of the central nervous system and dementia due to other causes in HIV-seronegative patients were not associated with increased CSF NPY-LI. Our data suggest that increased CSF NPY-LI is a relatively specific phenomenon of HIV encephalopathy and may be involved in the pathogenesis of HIV-related neurological dysfunction. The links between retroviral infection and increased expression of neuropeptide Y and their pathophysiological implications remain to be determined.

Topics: Adult; AIDS Dementia Complex; Chromatography, High Pressure Liquid; Female; HIV Infections; HIV Seronegativity; HIV Seropositivity; Humans; Male; Neuropeptide Y; Norepinephrine; Prospective Studies

HIV-associated sensory neuropathy is the most frequent manifestation of HIV disease, afflicting 40-50% of patients whose HIV disease is otherwise controlled by antiretroviral therapy. It often presents with significant neuropathic pain and is consistently associated with previous exposure to nucleoside reverse transcriptase inhibitors including stavudine (d4T), which is widely used in resource-limited settings. Here we investigated complex pain-related behaviours associated with d4T treatment using ethologically relevant thigmotaxis and burrowing behaviours in adult rats. Detailed neuropathological response was also examined using neurochemistry, electron microscopy, and proteomics. After 2 intravenous injections of d4T (50 mg/kg, 4 days apart), rats developed hind paw mechanical hypersensitivity, which plateaued at 21 days after initial d4T injection, a time that these animals also had significant changes in thigmotaxis and burrowing behaviours when compared to the controls; reductions in hind paw intraepidermal nerve fibre density and CGRP/IB4 immunoreactivity in L5 spinal dorsal horn, suggesting injury to both the peripheral and central terminals of L5 dorsal root ganglion neurons; and increases in myelinated and unmyelinated axon diameters in the sural nerve, suggesting axonal swelling. However, no significant glial and inflammatory cell response to d4T treatment was observed. Sural nerve proteomics at 7 days after initial d4T injection revealed down-regulated proteins associated with mitochondrial function, highlighting distal axons vulnerability to d4T neurotoxicity. In summary, we have reported complex behavioural changes and a distinctive neuropathology in a clinically relevant rat model of d4T-induced sensory neuropathy that is suitable for further pathophysiological investigation and preclinical evaluation of novel analgesics.

Topics: Activating Transcription Factor 3; Animals; Anti-HIV Agents; Brain; Calcitonin Gene-Related Peptide; Disease Models, Animal; Exploratory Behavior; Ganglia, Spinal; Gene Expression Regulation, Viral; HIV Infections; Hyperalgesia; Lectins; Male; Nerve Tissue Proteins; Neuralgia; Neuropeptide Y; Psychomotor Performance; Rats; Rats, Wistar; Reproducibility of Results; Sensory Receptor Cells; Stavudine; Sural Nerve; Time Factors

Hyperplasia of vascular smooth muscle cells (VSMCs) occurs during HIV infection, part of a spectrum of HIV-mediated cardiovascular and microvascular pathologies. These changes are not due to direct viral infection but may involve the receptor-mediated action of viral proteins, such as the envelope protein gp120. We sought to identify gp120 receptors which might mediate the vascular smooth muscle cell hyperplasia present in HIV infection. A homology between neuropeptide Y (NPY) and the previously identified receptor-active V2-region of gp120 defined by an octapeptide sequence (Peptide T) related to VIP was noted. Since NPY is mitogenic for VSMCs we therefore determined whether gp120 shares this activity. Rat aortic VSMCs were treated for 24 h with human (h)NPY and gp120 in the presence of 0.5% serum to measure [3H]thymidine incorporation, an index of cell proliferation. NPY increased [3H]thymidine incorporation by 80% after a 24-h treatment in a bimodal fashion, with peak effects at 10(-10) M and 10(-8) M. Gp120 was an even more potent mitogen for VSMCs with peak activity occurring at 10(-12) M. Peptide T was equipotent with gp120, and slightly less efficacious, suggesting that this domain may mediate gp120 effects on VSMCs. When combined, gp120 and NPY acted to antagonize one another, lowering DNA synthesis to basal levels. The profile of pharmacologic inhibition supports a role for NPY receptors since antagonists of Y1 and Y2 subtypes substantially or completely inhibited gp120-mediated VSMC proliferation. This is the first demonstration of the proliferative effects of HIV viral protein gp120 on VSMCs. The effect appears to be mediated via gp120 sequences related to VIP, peptide T, and NPY. These ligands may be competitive inhibitors of binding or gp120 processing. Novel treatments may emerge based upon VIP and NPY receptor antagonists if further work substantiates a role for gp120 in the vascular abnormalities of AIDS.

Topics: Amino Acid Sequence; Animals; Cardiovascular Diseases; Cell Division; Cells, Cultured; HIV; HIV Envelope Protein gp120; HIV Infections; Humans; Hyperplasia; Mitogens; Molecular Sequence Data; Muscle, Smooth, Vascular; Neuropeptide Y; Peptide T; Rats; Receptors, Neuropeptide Y; Sequence Homology, Amino Acid; Vasoactive Intestinal Peptide

The in vitro effect of neuropeptide Y (NPY) on natural killer (NK) cell activities of normal lymphocytes was investigated. NPY at 10(-9) to 10(-12) M concentrations produced significant suppression of NK activity against K 562 target cells. NPY at 10(-9) to 10(-12) M concentrations also produced significant inhibitory effects on NK activities of NK-enriched large granular lymphocytes against LAV-infected 8E5/LAV target cells. The suppression was dose dependent against both targets. NPY-induced suppression of NK activity of lymphocytes against K 562 target cells was specifically reversed by rabbit anti-NPY antisera at 1:800 and 1:1600 dilutions, showing the specificity of reactions. Pretreatment of target cells with NPY concentrations capable of inhibiting NK activity did not affect the sensitivity of K 562 target cells for lysis by effector cells. Inhibition of cytotoxicity was not due to direct toxicity of effector cells, because lymphocytes treated with NPY showed normal levels of 51Cr release and their viability was comparable to that of untreated control cells. These studies demonstrated that NPY, a product of sympathetic nervous system activation, may have a significant immunoregulatory effect on NK cell activities of normal lymphocytes that may be of clinical significance.

Topics: Adult; Cell Line; Cytotoxicity Tests, Immunologic; Cytotoxicity, Immunologic; Depression, Chemical; HIV Infections; Humans; Killer Cells, Natural; Male; Neuroimmunomodulation; Neuropeptide Y; Tumor Cells, Cultured