Opiate use and abuse has been known to suppress a number of immune responses and, therefore, have been postulated to serve as cofactor in the progression of HIV-1 infection. According to latest CDC statistics, since the HIV epidemic began, injection drug use has directly and indirectly accounted for more than one-third (36%) of AIDS cases in the United States. The high frequency of bacterial sepsis observed in HIV-positive patients has been shown to be in part due to impairment of innate immunity, specifically macrophage function (chemotaxis, bacterial killing, phagocytosis, and superoxide production). Our goal is to better understand effects of opioids on innate immunity in presence of HIV-1 envelope protein gp120.
The specific aims of this proposal will focus on experiments that specifically address mechanisms of morphine and gp120 induced suppression of macrophage's ability to internalize, and eliminate bacterial infections. Macrophage cell lines as well as primary peritoneal macrophages treated in vivo and in vitro will e used to show the effects of chronic morphine and gp120 on this constituent of innate immunity.
In aim one, we intend to investigate in vivo and in vitro effects of chronic morphine and gp120 on Fc-gamma receptor (FcgR) mediated phagocytosis of IgG opsonized bacterial particles. We will examine the role of morphine and gp120 in modulation of cAMP, FcgR expression and activation as well as actin polymerization. Additionally in aim two, we propose to study the effects of chronic morphine and gp120 on phago-lysosomal fusion and mechanisms of bacterial killing. Focusing on release of reactive oxygen intermediates (ROIs), reactive nitrogen intermediates (RNIs) and overall bactericidal ability of macrophages. In addition, we will study the effects of gp120 and if and how it modulates morphine induced inhibition of bacterial killing. By performing a detailed analysis of phagocytosis and bactericidal activity in presence of morphine and gp120 we hope to gain insight in general effect of opiates on bacterial clearance by macrophages during HIV infection.
HIV weakens the body's ability to fight disease by targeting immune cells in charge of bacterial clearance. Infections which are rarely seen in those with normal immune systems are deadly to those with HIV. In presence of drugs of abuse such as opioids, this effect is further exacerbated. Mechanisms of interaction between HIV and drugs of abuse have not been well explored. It is important to study the mechanisms of opioid and HIV induced immune suppression so we can design better therapies and improve quality of life.
| Ninkovi?, Jana; Roy, Sabita (2014) High throughput fluorometric technique for assessment of macrophage phagocytosis and actin polymerization. J Vis Exp :e52195 |
| Ninkovi?, Jana; Roy, Sabita (2013) Role of the mu-opioid receptor in opioid modulation of immune function. Amino Acids 45:9-24 |
| Ninkovi?, Jana; Roy, Sabita (2012) Morphine decreases bacterial phagocytosis by inhibiting actin polymerization through cAMP-, Rac-1-, and p38 MAPK-dependent mechanisms. Am J Pathol 180:1068-79 |
