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    • br Discussion Naloxone and CTAP were able to alter the

    2021-11-20


    Discussion Naloxone and CTAP were able to alter the febrile response induced by gp120. This effect was particularly evident during the initial hours following gp120 administration (90–210min). We also investigated the potential role of the delta-2 opioid receptor in gp120-induced fever. The delta-2 opioid receptors do not seem to be involved, as pretreatment with NTB did not show any effect on the febrile response. From these data, it appears that mu-opioid receptors participate in the initiation of the development of gp120-induced fever, and confirm the earlier data that the opioid system is involved in initiating the pathogenesis of fever (Benamar et al., 2000, Blatteis and Romanovsky, 1994). gp120 is implicated in the pathogenesis of neurological disorders associated with HIV and is capable of initiating neurotoxic cascades via an interaction with the CXCR4 and/or CCR5 chemokine receptors. Our recent data demonstrated that CXCR4 receptors in the POAH contribute to the pathogenesis of fever induced by gp120 (Benamar et al., 2010). In situ hybridization and immunocytochemistry showed that CXCR4 neuronal expression is mainly found in several Ethacrynic Acid areas, including the POAH (Banisadr et al., 2002, Guyon et al., 2005). A functional interaction between the opioid system and chemokine receptors (particularly those involved in HIV life-cycle, CCR5 and CXCR4) is well documented (Szabo et al., 2002, Adler et al., 2006, Chen et al., 2007). The mu-opioid and chemokine receptors are both members of the GPCR superfamily, expressed in the POAH and implicated in the pathogenesis of fever. Together, these data raise the possibility that a functional interaction is likely to occur between gp120 (via CXCR4 or/and CCR5) and mu-opioid receptors at the level of GPCR in the POAH during the development of the febrile response. HIV and drug abuse are not isolated problems, but they interact and influence each other. Current available data indicating that opioid can exacerbate the central nervous system complications of HIV-1 infection. Wasting syndrome is a common complication of HIV infection and is marked by progressive weight loss and weakness, often associated with fever. Recently, we found that direct infusion of gp120 into POAH induces fever, indicating that this viral protein contributes to generation of fever associated with HIV-wasting syndrome (Benamar et al., 2010). Previously we have shown that mu-opioid receptors are the target for morphine-induced hyperthermia (Benamar et al., 2007). These data together with the present results suggest that the use or abuse of morphine may potentiate the fever associated with HIV-wasting syndrome.
    Contributors
    Conflict of interest
    As the initial binding envelope protein for viral entry, HIV-1 gp120 is an attractive target for developing novel methods of HIV-1 detection., , The entry of HIV-1 into host immune cells begins with the specific binding of gp120 envelope protein to cellular CD4 receptors on the surface of macrophages and T cells. Although the surface of gp120 is extensively glycosylated to avoid binding by antibodies, the conserved CD4 binding domain remains intact. The X-ray crystallographic structure of the CD4–gp120 complex shows a large interacting surface between the CD4 domain 1 (involving 22 amino acid residues) and HIV-1 gp120 (involving 26 amino acid residues)., This large interacting surface results in a high specificity and affinity of CD4–gp120 interaction. In a previous study, a mutant CD4 domain 1 (mD1.2, 12KDa) protein showed about 50-fold stronger binding affinity for HIV-1 gp120 than the soluble CD4 (sCD4) receptor. The small size, favorable solubility and strong affinity of this mD1.2 protein makes it an ideal probe to detect HIV-1 gp120 protein. Förster resonance energy transfer (FRET) has been used extensively to study the structure and binding of proteins., , As a fluorescence acceptor, the amino acid acridon-2-ylalanine (Acd) is an attractive fluorophore because of its high quantum yield, high photostability and small size. Its small size enables it to minimally perturb the folding of proteins in which it is incorporated. In this study, we prepared a fluorescent mD1 protein sensor that can specifically bind to the conserved domain of HIV gp120 protein. This fluorescent probe contains an acridon-2-ylalanine and a tryptophan that form a FRET pair. Once bound to gp120 protein, the fluorescence intensity of the sensor is decreased. Thus, this method could be used to detect the gp120 protein of HIV virus directly. It does not require any response from the human immune system which can take several weeks following infection, thus potentially enabling the detection of HIV infection at an early stage.