Abstract
The US is currently experiencing a serious epidemic of methamphetamine (Meth) use entangled with HIV-1 infection. Blood monocyte derived dendritic cells (DC ) are the first line of defense against HIV-1 infection and are the initial target of HIV-1 in injection drug users. Chemokines are known to be HIV-1 suppressing molecules and are positively associated with non- progression of HIV disease. Co-stimulatory molecules are necessary for DC maturation, effective antigen presentation, cell migration, and T cell proliferation. Although previous studies suggest that Meth deregulates various immune responses, the role of Meth on gene expression and production of β-chemokines and co-stimulatory molecules by DC has not been studied. We hypothesize that Meth induced immune defects may be mediated by dysregulation of β-chemokines (MIP-1α/CCL3, MIP-1β/CCL4 and RANTES/CCL5), co-stimulatory and maturation molecules (CD83 and CCR7) by DC. Our results show that Meth significantly downregulates the gene expression and production of β-chemokines and co stimulatory molecule by DC from normal subjects. In HIV-1 infected subjects, RANTES variant In1.1c that has been associated with accelerated HIV-1 disease progression was significantly higher compared to normal controls. Further, Meth significantly inhibited total RANTES gene expression with a reciprocal upregulation of RANTES variant In1.1c in a dose dependent manner by both immature DC (IDC) and mature DC (MDC) from normal subjects. These studies report for the first time that Meth deregulates β-chemokines and co-stimulatory molecule expression by DC. The results emanating from these studies may help to support the therapeutic application of chemokines to restore anti-HIV-1 immune responses to prevent or control HIV-1 infection in meth using populations.
Highlights
The US is currently experiencing a grave epidemic of methamphetamine (Meth) use as a recreational drug [1]
While the capacity of dendritic cells (DC) to migrate is regulated by the expression of a number of cytokines and chemokines, further activation is regulated by various co stimulatory molecules
Meth suppresses the expression of co-stimulatory molecule, CD83 and the maturation marker, CCR7 on DC: Since the co stimulatory molecule CD83, a hallmark of mature DC (MDC), plays a significant role in antigen presentation, stimulation of T cells and anti-HIV-1 immune responses, we examined the in vitro effect of Meth on the expression of the CD83 molecule on DC by flow cytometry analysis
Summary
The US is currently experiencing a grave epidemic of methamphetamine (Meth) use as a recreational drug [1]. US Drug Enforcement Administration reports that as of May 2006, Meth use has surpassed cocaine and heroin use combined as a street or club drug. DC express a number of co stimulatory molecules such as CD40, CD80 (B7.1), CD86 (B7.2) and chemokine receptor, CCR7 that are required for efficient antigen presentation by DC. The important role of DC as the first line of defense against HIV-1 infections has recently been recognized. Defective expression or modulation of chemokines and co stimulatory molecules by DC may cause defective antigen presentation that can lead to defective activation of HIV-1 specific T cells. Chemokines have gained major attention recently because of their specific inhibitory effects on HIV-1 infection [7,8].
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