beta-endorphin and HIV-Infections

Chronic widespread pain (CWP) is associated with a high rate of disability and decreased quality of life in people with HIV-1 (PWH). We previously showed that PWH with CWP have increased hemolysis and elevated plasma levels of cell-free heme, which correlate with low endogenous opioid levels in leukocytes. Further, we demonstrated that cell-free heme impairs β-endorphin synthesis/release from leukocytes. However, the cellular mechanisms by which heme dampens β-endorphin production are inconclusive. The current hypothesis is that heme-dependent TLR4 activation and macrophage polarization to the M1 phenotype mediate this phenomenon. Our novel findings showed that PWH with CWP have elevated M1-specific macrophage chemokines (ENA-78, GRO-α, and IP-10) in plasma. In vitro, hemin-induced polarization of M0 and M2 macrophages to the M1 phenotype with low β-endorphins was mitigated by treating cells with the TLR4 inhibitor, TAK-242. Similarly, in vivo phenylhydrazine hydrochloride (PHZ), an inducer of hemolysis, injected into C57Bl/6 mice increased the M1/M2 cell ratio and reduced β-endorphin levels. However, treating these animals with the heme-scavenging protein hemopexin (Hx) or TAK-242 reduced the M1/M2 ratio and increased β-endorphins. Furthermore, Hx attenuated heme-induced mechanical, heat, and cold hypersensitivity, while TAK-242 abrogated hypersensitivity to mechanical and heat stimuli. Overall, these results suggest that heme-mediated TLR4 activation and M1 polarization of macrophages correlate with impaired endogenous opioid homeostasis and hypersensitivity in people with HIV.

Topics: Analgesics, Opioid; Animals; beta-Endorphin; Heme; Hemolysis; HIV Infections; Homeostasis; Macrophages; Mice; Pain; Phenotype; Quality of Life; Toll-Like Receptor 4

The prevalence of chronic widespread pain (CWP) in people with HIV is high, yet the underlying mechanisms are elusive. Leukocytes synthesize the endogenous opioid, β-endorphin, within their endoplasmic reticulum (ER). When released into plasma, β-endorphin dampens nociception by binding to opioid receptors on sensory neurons. We hypothesized that the heme-dependent redox signaling induces ER stress, which attenuates leukocyte β-endorphins levels/release, thereby increasing pain sensitivity in people with HIV. Results demonstrated that HIV positive individuals with CWP had increased plasma methemoglobin, erythrocytes membrane oxidation, hemolysis, and low plasma heme scavenging enzyme, hemopexin, compared to people with HIV without CWP and HIV-negative individuals with or without pain. In addition, the leukocytes from people with HIV with CWP had attenuated levels of the heme metabolizing enzyme, heme oxygenase-1, which metabolizes free heme to carbon-monoxide and biliverdin. These individuals also had elevated ER stress, and low β-endorphin in leukocytes. In vitro, heme exposure or heme oxygenase-1 deletion, decreased β-endorphins in murine monocytes/macrophages. Treating cells with a carbon-monoxide donor or an ER stress inhibitor, increased β-endorphins. To mimic hemolytic effects in a preclinical model, C57BL/6 mice were injected with phenylhydrazine hydrochloride (PHZ). PHZ increased cell-free heme and ER stress, decreased leukocyte β-endorphin levels and hindpaw mechanical sensitivity thresholds. Treatment of PHZ-injected mice with hemopexin blocked these effects, suggesting that heme-induced ER stress and a subsequent decrease in leukocyte β-endorphin is responsible for hypersensitivity in people with HIV.

Topics: Animals; beta-Endorphin; Heme; HIV Infections; Leukocytes; Mice; Mice, Inbred C57BL; Pain

Acute and chronic alcohol abuse impairs various functions of the immune system and thus, has been implicated as a cofactor in the immunopathogenesis of human immunodeficiency virus (HIV) disease progression. We determined whether naltrexone, an opioid receptor antagonist widely used in the treatment of alcoholism, inhibits alcohol-mediated enhancement of HIV infection of T cells. Alcohol enhanced HIV infection of peripheral blood lymphocytes (PBL) and a human lymphoid cell line (CEMX174). Alcohol increased HIV X4 envelope (Env), not murine leukemia virus Env-pseudotyped infection of CEMX174 cells. Naltrexone antagonized the enhancing effect of alcohol on HIV infection of PBL and CEMX174 cells. The specific mu-opioid receptor antagonist, Cys2, Tyr3, Arg5, Pen7 (CTAP) amide, also blocked the enhancing effect of alcohol on HIV infection. Investigation of the underlying mechanism for the alcohol action showed that alcohol significantly increased endogenous beta-endorphin production and induced mu-opioid receptor mRNA expression in PBL and CEMX174 cells. The role of beta-endorphin in alcohol-mediated enhancement of HIV infection was indicated by the observations that naltrexone and CTAP antagonized ether alcohol- or exogenous beta-endorphin-mediated enhancement of HIV infection. These findings suggest a biological mechanism for the potential therapeutic benefit of naltrexone in treating HIV-infected alcoholics.

Topics: Adult; Alcohol Deterrents; Alcoholism; beta-Endorphin; Cells, Cultured; Disease Susceptibility; Drug Evaluation, Preclinical; Ethanol; Female; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Hybrid Cells; Leukemia Virus, Murine; Lymphocytes; Male; Middle Aged; Naltrexone; Peptide Fragments; Peptides; Receptors, Opioid, mu; RNA, Messenger; Somatostatin; T-Lymphocytes; Up-Regulation; Virion; Virus Replication

Topics: Acquired Immunodeficiency Syndrome; beta-Endorphin; Demography; Environment; Health Services Needs and Demand; Hepatitis C; Hispanic or Latino; HIV Infections; Humans; Research; Substance-Related Disorders

Topics: Alzheimer Disease; beta-Endorphin; beta-Lipotropin; beta-MSH; Diabetes Mellitus; HIV Infections; Humans; Neuropeptides; Obesity; Pituitary Gland; Pro-Opiomelanocortin; Protein Precursors; Serine Endopeptidases

Topics: beta-Endorphin; Cells, Cultured; Female; Fetus; HIV Infections; HIV-1; Humans; Interleukin-1; Interleukin-6; Microglia; Pregnancy; Receptors, Opioid; Virus Replication

We investigated beta-endorphin (BE) content in an HIV-infected cell line and in peripheral blood mononuclear cells (PBM) from HIV-positive subjects. HIV infection increased BE content in HuT78 cell line compared to uninfected cells. Accordingly, BE content was greater in HIV-positive subjects than in healthy controls, both in fresh PBM and in mitogen-stimulated or unstimulated cultured cells. Further, in PHA-stimulated cultures, BE increase was correlated with disease progression. Opioids are known to decrease immune responsiveness in vivo, and it may be that the increased BE concentrations contribute to HIV-associated immune deficiency. In HIV-positive subjects, but not in healthy controls, intracellular BE concentration was positively correlated with PHA-induced PBM proliferation. The latter data suggest an alternative explanation: that the increased BE content represents a paradoxical response of the host in an attempt to balance virus-induced immunodepression. Thus, BE may be important in fine-tuning of the immune response with its up- and downregulation dependent upon differences in immune status.

Topics: Adult; beta-Endorphin; Cell Line; Female; HIV Infections; HIV Seronegativity; HIV Seropositivity; Humans; Immune Tolerance; Lymphocytes; Male; Reference Values; Substance Abuse, Intravenous