Reduction of Immune Activation with Chloroquine Therapy during Chronic HIV Infection

Human Immunology Section, NIH Vaccine Research Center, Bethesda, MD 20892-3005, USA.
Journal of Virology (Impact Factor: 4.44). 11/2010; 84(22):12082-6. DOI: 10.1128/JVI.01466-10
Source: PubMed


Increased levels of activated T cells are a hallmark of the chronic stage of human immunodeficiency virus (HIV) infection
and are highly correlated with HIV disease progression. We evaluated chloroquine (CQ) as a potential therapy to reduce immune
activation during HIV infection. We found that the frequency of CD38+ HLA-DR+ CD8 T cells, as well as Ki-67 expression in CD8 and CD4 T cells, was significantly reduced during CQ treatment. Our data
indicate that treatment with CQ reduces systemic T-cell immune activation and, thus, that its use may be beneficial for certain
groups of HIV-infected individuals.

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Available from: William M Stauffer
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    • "We also tested chloroquine, an antimalarial drug which exhibits anti-inflammatory and anti-HIV effects in vitro and in vivo. For example, chloroquine administration has been reported to reduce T-cell activation in chronic HIV-infected patients [47]. In a rodent model, chloroquine prevented a bacterial toxin-induced intracerebral toxicity [17]. "
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    ABSTRACT: Background Neuroinflammation is a common immune response associated with brain human immunodeficiency virus-1 (HIV-1) infection. Identifying therapeutic compounds that exhibit better brain permeability and can target signaling pathways involved in inflammation may benefit treatment of HIV-associated neurological complications. The objective of this study was to implement an in vivo model of brain inflammation by intracerebroventricular administration of the HIV-1 viral coat protein gp120 in rats and to examine anti-inflammatory properties of HIV adjuvant therapies such as minocycline, chloroquine and simvastatin. Methods Male Wistar rats were administered a single dose of gp120ADA (500 ng) daily for seven consecutive days, intracerebroventricularly, with or without prior intraperitoneal administration of minocycline, chloroquine or simvastatin. Maraviroc, a CCR5 antagonist, was administered intracerebroventricularly prior to gp120 administration for seven days as control. Real-time qPCR was used to assess gene expression of inflammatory markers in the frontal cortex, hippocampus and striatum. Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) secretion in cerebrospinal fluid (CSF) was measured applying ELISA. Protein expression of mitogen-activated protein kinases (MAPKs) (extracellular signal-related kinase 1/2 (ERK1/2), c-Jun N-terminal kinases (JNKs) and P38 kinases (P38Ks)) was detected using immunoblot analysis. Student’s t-test and ANOVA were applied to determine statistical significance. Results In gp120ADA-injected rats, mRNA transcripts of interleukin-1β (IL-1β) and inducible nitric oxide synthase (iNOS) were significantly elevated in the frontal cortex, striatum and hippocampus compared to saline or heat-inactivated gp120-injected controls. In CSF, a significant increase in TNF-α and IL-1β was detected. Maraviroc reduced upregulation of these markers suggesting that the interaction of R5-tropic gp120 to CCR5 chemokine receptor is critical for induction of an inflammatory response. Minocycline, chloroquine or simvastatin attenuated upregulation of IL-1β and iNOS transcripts in different brain regions. In CSF, minocycline suppressed TNF-α and IL-1β secretion, whereas chloroquine attenuated IL-1β secretion. In gp120-injected animals, activation of ERK1/2 and JNKs was observed in the hippocampus and ERK1/2 activation was significantly reduced by the anti-inflammatory agents. Conclusions Our data demonstrate that anti-inflammatory compounds can completely or partially reverse gp120-associated brain inflammation through an interaction with MAPK signaling pathways and suggest their potential role in contributing towards the prevention and treatment of HIV-associated neurological complications.
    Full-text · Article · May 2014 · Journal of Neuroinflammation
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    • "So far, studies employing these and other anti-inflammatory molecules have rendered contrasting results (Hatano, 2013). Thus, chloroquine administration has been shown to decrease levels of T cell activation (Murray et al., 2010) but produce faster CD4þ T cell loss when used for longer periods of time (Paton et al., 2012). A better knowledge of the best timing to implement interventions aimed at decreasing persistent immune activation is warranted. "
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    ABSTRACT: Thirty years after the identification of HIV, a cure for HIV infection is still to be achieved. Advances of combined antiretroviral therapy (cART) in recent years have transformed HIV infection into a chronic disease when treatment is available. However, in spite of the favorable outcomes provided by the newer therapies, cART is not curative and patients are at risk of developing HIV-associated disorders. Moreover, universal access to antiretroviral treatment is restricted by financial obstacles. This review discusses the most recent strategies that have been developed in the search for an HIV cure and to improve life quality of people living with HIV.
    Full-text · Article · Apr 2014 · Virology
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    • "Clinical trials have supported the use of chloroquine to reduce immune activation in HIV-infected patients. When chloroquine was administered to ART-naïve subjects for 2 months, patients showed immunological improvement, as the frequency of CD38+ HLA-DR + CD8+ T cells, proliferation of T cells, and circulating LPS levels were signi fi cantly reduced (Murray et al. 2010 ) . Six months of chloroquine administration to HIV-infected clinical nonresponders, who had inadequate reconstitution of CD4+ T cells despite suppressive ART, had decreased frequency of activated T cells, decreased circulating LPS, decreased production of in fl ammatory cytokines (IL-6, TNF-alpha) in response to ex vivo stimulation of TLR ligands, and evidenced improved CD4+ T cell counts and pDC numbers (Piconi et al. 2011 ) . "
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    ABSTRACT: Plasmacytoid dendritic cells (pDCs) are innate immune cells that are specialized to produce interferon-alpha (IFNα) and participate in activating adaptive immune responses. Although IFNα inhibits HIV-1 (HIV) replication in vitro, pDCs may act as inflammatory and immunosuppressive dendritic cells (DCs) rather than classical antigen-presenting cells during chronic HIV infection in vivo, contributing more to HIV pathogenesis than to protection. Improved understanding of HIV-pDC interactions may yield potential new avenues of discovery to prevent HIV transmission, to blunt chronic immune activation and exhaustion, and to enhance beneficial adaptive immune responses. In this chapter we discuss pDC biology, including pDC development from progenitors, trafficking and localization of pDCs in the body, and signaling pathways involved in pDC activation. We focus on the role of pDCs in HIV transmission, chronic disease progression and immune activation, and immunosuppression through regulatory T cell development. Lastly, we discuss potential future directions for the field which are needed to strengthen our current understanding of the role of pDCs in HIV transmission and pathogenesis.
    Full-text · Article · Jan 2013 · Advances in Experimental Medicine and Biology
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