Expression of the mu opioid receptor in the human immunodeficiency virus type 1 transgenic rat model.

The mu opioid receptor (MOR) mediates the actions of opioids such as morphine and is expressed in the central nervous system as well as on various cells of the immune system, including lymphocytes and macrophages (6, 28, 29, 37, 42, 48). In the immune system, activation of the MOR suppresses lymphocyte proliferation, decreases antibody production (9), and decreases macrophage-mediated immunity (18, 28, 38). Previous reports by Suzuki et al. have even shown that morphine changes the progression of human immunodeficiency virus (HIV) infection to AIDS in monkey models (14, 44). Expression of the MOR can be modulated by various cytokines, including interleukin-1β (IL-1β) (46), tumor necrosis factor alpha (TNF-α) (26), IL-4 (27), and IL-6 (7). In response to microbial infections, both bacterial and viral, these proinflammatory cytokines, along with anti-inflammatory cytokines such as IL-10, are produced by the host's cells (15, 24). The balance between proinflammatory cytokines and anti-inflammatory cytokines may be directly related to the progression of HIV infection to AIDS (8). The bacterial endotoxin lipopolysaccharide (LPS) is a well-characterized active complex glycolipid isolated from the outer membrane of gram-negative bacteria (19, 33). LPS is routinely used as a surrogate to study gram-negative bacterial infection, since it can induce an inflammatory response, such as production of cytokines (19, 31). We and others have previously shown that systemic administration of LPS induces secretion of TNF-α, IL-1β, and IL-6 into the circulation (23, 30, 45) and increases the expression of these cytokines in the brain (11, 45). Macrophages play an essential role in modulating the initiation and perpetuation of the inflammatory response to bacterial infection. Rat peritoneal macrophages have been shown to respond to LPS by secreting proinflammatory cytokines, including TNF-α (45). In turn, these cytokines have also been demonstrated to mediate the actions of LPS (18). HIV-1 infection results from the actions of HIV-1 viral proteins, including the envelope protein, glycoprotein 120 (gp120), on the host's T cells and macrophages (12). gp120 mediates the binding of HIV-1 to CD4 receptors and chemokine coreceptors to initiate the entry of the virus into the immune cells (13). Unlike T cells, macrophages are relatively resistant to the cytopathic effects of the HIV-1 virus (39). HL-60 promyelocytic leukemia cells are well-characterized, immortal cells capable of differentiating into macrophage-like cells by treatment with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) (4, 5). We previously reported that MOR is expressed in TPA-differentiated HL-60 (TPA-HL-60) cells, and recently we showed that HIV gp120 induces the secretion of TNF-α from these cells, which then up-regulates the expression of the MOR in an autocrine/paracrine manner (3). A novel, noninfectious HIV transgenic (HIV-1Tg) rat model was recently created by Reid et al. (36). The HIV-1Tg rat model carries an HIV-1 genome with gag and pol deleted under the control of the HIV-1 viral promoter and expresses seven of the nine HIV genes, including gp120 (36). Thus, there is no viral replication in the HIV-1Tg rat model. Even though the macrophages do not act as a viral reservoir in this animal model, the viral proteins are expressed in various organs and are present in the circulating blood (36). In addition, the HIV-1Tg rat develops many characteristics similar to those of humans infected with HIV-1, including expression of viral genes, immune response alterations, pathologies with advancing age (36), T-cell abnormalities (35), and kidney failure (34). There are also extensive and progressive neurobehavioral and neuropathologic changes within the brain parenchyma of these animals (36). Studies using the peritoneal macrophages isolated from the HIV-1Tg rat may lead to a better understanding of the functional roles of these immune cells in the course of HIV infection other than as viral reservoirs. Thus, these two models, HIV-1Tg rat peritoneal macrophages and TPA-HL-60 cells, are unique tools for studying the effects of an HIV viral protein such as gp120 on the immune system.