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

Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA,
Virology (Impact Factor: 3.32). 02/2005; 331(1):106-16. DOI: 10.1016/j.virol.2004.10.013
Source: PubMed


To date, attempts to eliminate HIV-1 infection from its latent reservoirs, a prerequisite for the development of a curative treatment strategy for HIV-1 infection, have been unsuccessful. We demonstrate that the FDA approved antifungal agent amphotericin B efficiently reactivates HIV-1 infection in THP89GFP cells, a model of HIV-1 latency in macrophages. Although amphotericin B does not directly reactivate latent HIV-1 infection in T cells (e.g., J89GFP), amphotericin-B-stimulated macrophages (THP89GFP cells or primary macrophages) when cocultured with J89GFP cells can induce HIV-1 reactivation in these cells in trans. Because of the close proximity of antigen presenting macrophages and T cells in the primary lymphoid organs, such interaction between antigen presenting macrophages and T cells are frequent, and it seems reasonable to assume that trans-reactivation strategies hold promise to also reactivate latent HIV-1 infection in vivo.

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    • "Several broad spectrum therapeutic molecules are being investigated as potential candidates to eliminate latent HIV-reservoirs. Various strategies such as T-cell activation including IL-7, [16], [17], Amphotericin B [60], PKC activating phorbol ester derivatives such as prostratin and plant derived products like Jatrophane diterpene SJ23B [61], [62] and histone deacetylase (HDAC) inhibitors such as SAHA and Valproic acid [36], [37], [63] and 5HN (via oxidative stress and NF-κB independent pathway) [7] have been shown to reactivate latent HIV-1 infection. However, none of these strategies provided sufficient reactivation to be considered viable candidates for clinical purposes. "
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    ABSTRACT: HIV's ability to establish long-lived latent infection is mainly due to transcriptional silencing in resting memory T lymphocytes and other non dividing cells including monocytes. Despite an undetectable viral load in patients treated with potent antiretrovirals, current therapy is unable to purge the virus from these latent reservoirs. In order to broaden the inhibitory range and effectiveness of current antiretrovirals, the potential of bryostatin was investigated as an HIV inhibitor and latent activator. Bryostatin revealed antiviral activity against R5- and X4-tropic viruses in receptor independent and partly via transient decrease in CD4/CXCR4 expression. Further, bryostatin at low nanomolar concentrations robustly reactivated latent viral infection in monocytic and lymphocytic cells via activation of Protein Kinase C (PKC) -alpha and -delta, because PKC inhibitors rottlerin and GF109203X abrogated the bryostatin effect. Bryostatin specifically modulated novel PKC (nPKC) involving stress induced AMP Kinase (AMPK) inasmuch as an inhibitor of AMPK, compound C partially ablated the viral reactivation effect. Above all, bryostatin was non-toxic in vitro and was unable to provoke T-cell activation. The dual role of bryostatin on HIV life cycle may be a beneficial adjunct to the treatment of HIV especially by purging latent virus from different cellular reservoirs such as brain and lymphoid organs.
    PLoS ONE 06/2010; 5(6):e11160. DOI:10.1371/journal.pone.0011160 · 3.23 Impact Factor
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    • "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. "
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    ABSTRACT: 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.
    International journal of biological sciences 09/2009; 5(6):603-10. · 4.51 Impact Factor
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    ABSTRACT: 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.
    Journal of Biological Chemistry 11/2005; 280(41):34420-6. DOI:10.1074/jbc.M506689200 · 4.57 Impact Factor
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