Amphotericin-B-mediated reactivation of latent HIV-1 infection

Jones, Jennifer; Kosloff, Barry; Benveniste, Etty N.; Shaw, George M.; Kutsch, Olaf

doi:10.1016/j.virol.2004.10.013

Cited by 13 publications

(12 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…8 Primary human macrophages were generated by plating 10 ϫ 10 6 peripheral blood mononuclear cells/well and culturing the cells in Dulbecco modified Eagle medium (DMEM) as described previously. 25 The purity of the macrophage cultures is 95% or higher, as determined by staining for CD14. The murine microglia cell line EOC13 and macrophage cell line RAW264.7 were maintained in DMEM supplemented with 10% fetal bovine serum as described previously.…”

Section: Cellsmentioning

confidence: 99%

LPS induces CD40 gene expression through the activation of NF-κB and STAT-1α in macrophages and microglia

Qin

Wilson

Lee

et al. 2005

Blood

194

185

View full text Add to dashboard Cite

IntroductionCD40 is a member of the tumor necrosis factor receptor (TNFR) superfamily that is expressed by cells, including B cells, macrophages, microglia, dendritic cells, endothelial cells, and tumor cells. The interaction between CD40 and its cognate ligand, CD40L (CD154), is critical for a productive immune response. 1,2 Upregulation of various cell surface molecules, such as class II major histocompatibility complex, CD40, CD80, and CD86, occurs on CD40-CD154 contact, as well as the production of numerous cytokines and chemokines (interleukin 1 [IL-1], IL-6, IL-10, tumor necrosis factor ␣ [TNF-␣] and macrophage inflammatory protein 1 [MIP-1]) and cytotoxic radicals. 2 CD40 has been implicated in participating in many human diseases, particularly autoimmune diseases. 3,4 Blocking the interaction between CD40-CD154 with anti-CD154 or anti-CD40 antibody is beneficial in animal models of autoimmune diseases. 5 These findings illustrate the importance of CD40-CD154 interactions for homeostasis of immune responses. We have previously shown that macrophages and microglia, the endogenous macrophage of the brain, constitutively express CD40 at a low level, which is greatly enhanced by the cytokine interferon ␥ (IFN-␥). IFN-␥-induced CD40 expression involves IFN-␥-activated signal transducer and activator of transcription 1␣ (STAT-1␣) and nuclear factor-B (NF-B) activation through an autocrine response to IFN-␥-induced TNF-␣ production. [6][7][8][9] The immune response to microbial pathogens relies on both innate and acquired immunity. Innate immunity is determined by the interaction between potential pathogens and their cognate binding partners (receptors) on phagocytes, which is performed by a group of proteins, the Toll-like receptor (TLR) family. 10,11 At least 10 TLRs (TLR1-TLR10) recognize specific molecular patterns that are present in microbial components. Stimulation of different TLRs induces distinct patterns of gene expression, which not only leads to the activation of innate immunity but also instructs the development of antigen-specific acquired immunity. 12,13 The TLR family signals via shared downstream signaling molecules, including the adapter molecule myeloid differentiation primary-response protein 88 (MyD88), interleukin-1 receptor-associated protein kinases (IRAK1 and IRAK4), transforming growth factor ␤ (TGF-␤)-activated kinase (TAK1), TAK1-binding protein 1 (TAB1), TAB2, and tumor necrosis factor receptor-associated factor 6. 10,11 TAK1 is a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family, which is essential for IL-1, TNF-␣, and lipopolysaccharide (LPS)-induced activation of NF-B and MAPKs. 10 The NF-B family of transcription factors is composed of 5 members, p65 (Rel-A), Rel-B, c-Rel, p50, and p52, which function as homodimers and heterodimers. NF-B transcription factors are present in the cytoplasm in an inactive state, complexed with inhibitory IB proteins. The activation process is mediated by Supported by the National Institutes of Health (grants NS45290 and N...

show abstract

Section: Cellsmentioning

confidence: 99%

LPS induces CD40 gene expression through the activation of NF-κB and STAT-1α in macrophages and microglia

Qin

Wilson

Lee

et al. 2005

Blood

194

185

View full text Add to dashboard Cite

show abstract

“…Polyenes interfere with the sterol-rich membranes of enveloped viruses such as human immunodeficiency virus (HIV) (3). Recently, amphotericin B has been found to reactivate latent HIV in macrophages, and these polyene-stimulated cells in turn induce viral reactivation in T lymphocytes (11). Although the current highly active antiretroviral therapy effectively eliminates free virus, reservoirs of provirus must be reactivated to allow complete clearance (11).…”

mentioning

confidence: 99%

“…Recently, amphotericin B has been found to reactivate latent HIV in macrophages, and these polyene-stimulated cells in turn induce viral reactivation in T lymphocytes (11). Although the current highly active antiretroviral therapy effectively eliminates free virus, reservoirs of provirus must be reactivated to allow complete clearance (11). Amphotericin B derivatives may form part of a strategy for eradication, rather than suppression, of the virus in AIDS patients.…”

mentioning

confidence: 99%

Biosynthesis of Amphotericin Derivatives Lacking Exocyclic Carboxyl Groups

Carmody

Murphy

Byrne

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

Amphotericin B is a medically important antifungal antibiotic that is also active against human immunodeficiency virus, Leishmania parasites, and prion diseases. The therapeutic use of amphotericin B is restricted by severe side effects that can be moderated by liposomal formulation or structural alteration. Chemical modification has shown that suppression of charge on the exocyclic carboxyl group of amphotericin B substantially reduces toxicity. We report targeted deletions of the amphN cytochrome P450 gene from the chromosome of the amphotericin-producing bacterium Streptomyces nodosus. The mutant strains produced amphotericin analogues in which methyl groups replace the exocyclic carboxyl groups. These compounds retained antifungal activity and had reduced hemolytic activity.There are increasingly urgent requirements for new antibiotics to treat infectious disease (1). The need is especially acute with systemic fungal infections that are increasing in incidence and are often fatal (2). Of the few antifungals available at present, the most reliable is amphotericin B (compound 1 in Fig. 1), a polyene macrolide synthesized by Streptomyces nodosus (3). Amphotericin B disrupts ergosterol-containing fungal membranes and has a broad spectrum of activity. Whereas resistance to most non-polyene antifungals has appeared rapidly, the most prevalent fungal pathogens of humans have been slow to develop resistance to amphotericin B, even after more than three decades of clinical use (4). The advantages of amphotericin B are offset by toxicity that results from low water solubility and interactions with cholesterol in mammalian membranes. Toxicity has also prevented full exploitation of the antiviral, antiprion, and antiparasitic properties of amphotericin B (3). The adverse effects of the drug can be reduced by liposomal formulation, heat-induced superaggregation, or structural alteration (5). Chemical modification has shown that suppression of charge on the exocyclic carboxyl group reduces toxicity and improves antifungal specificity (6). Further improvements have been made by derivatization with additional sugars (7).Substantial reduction in amphotericin B toxicity would minimize adverse side effects on patients and also allow high dose treatment of infections by emerging fungal pathogens that are sensitive only to high concentrations of the drug. Non-toxic amphotericin analogues and formulations may also be useful in other therapeutic areas. Polyene antibiotics delay the onset of prion diseases in animal models (8). These effects are thought to result from interactions of polyenes with cholesterol-rich membrane microdomains that contain glycosylphosphatidylinositolanchored prion proteins (3, 9). Amphotericin B formulations are gaining favor for treatment of cutaneous and visceral leishmaniasis, particularly as resistance to other anti-Leishmania drugs continues to increase (10). Polyenes may also become important in treatment of viral infections. Polyenes interfere with the sterol-rich membranes of enveloped viruses suc...

show abstract

“…Although HIV infected prMCs may gradually lose the expression of viral chemokine coreceptors, the re-seeding or spread of the virus apparently requires the re-synthesis of the viral proteins and replication of the archival clone of the virus in the reservoir. The reactivation of latent HIV infection in the reservoir could be triggered by a number of factors, including T-cell activation, herpes-virus infection, or antifungal agent amphotericin B 25-27. Thus, it is likely that a significant number of latently infected mast cells at the stage of reactivation will express both mast and viral specific proteins, or at least, they would be physically blended within or immediately adjacent to HIV infected cells in different tissue sites of HIV patients.…”

Section: Discussionmentioning

confidence: 99%

Failure to detect active virus replication in mast cells at various tissue sites of HIV patients by immunohistochemistry

Nelson¹,

Auerbach²,

Man³

2009

Int. J. Biol. Sci.

View full text Add to dashboard Cite

A recent report postulated that the mast cell population is a significant reservoir for persistent HIV infection. Our study attempted to validate this hypothesis by quantitatively comparing the distribution of mast cells and cells expressing the HIV protein p24 in HIV infected patients. Consecutive sections of paraffin-embedded human tissues from various tissue sites were subjected to immunohistochemistry with monoclonal antibodies to mast cell tryptase, viral protein p24, and other molecules. The sub-cellular distribution of these molecules was examined, to determine whether immunoreactivities to these molecules would be co-localized within the same cells. Our study revealed that, in two immediate adjacent sections immunostained for mast cell tryptase and p24, respectively, all or nearly all tryptase and p24 expressing cells were distributed at different areas. In the single section double immunostained for mast cell tryptase and p24, 5 (1.1%) of 460 large p24 expressing cell clusters encountered showed a single or few mast cells within or adjacent to p24 expressing cell clusters, but no distinct co-localization of these two proteins was observed. Similarly, no distinct co-localization was observed in any of over 500 isolated individual mast cells and p24 expressing cells. In contrast, macrophages were consistently intermixed with or adjacent to p24 expressing cells, and p24 immunostaining were seen in the cytoplasm of a subset of macrophages. These findings suggest that tissue mast cells do not show evidence for active virus replication by the techniques employed.

show abstract

Amphotericin-B-mediated reactivation of latent HIV-1 infection

Cited by 13 publications

References 70 publications

LPS induces CD40 gene expression through the activation of NF-κB and STAT-1α in macrophages and microglia

LPS induces CD40 gene expression through the activation of NF-κB and STAT-1α in macrophages and microglia

Biosynthesis of Amphotericin Derivatives Lacking Exocyclic Carboxyl Groups

Failure to detect active virus replication in mast cells at various tissue sites of HIV patients by immunohistochemistry

Contact Info

Product

Resources

About