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: 3.28). 02/2005; 331(1):106-16.
Source: PubMed

ABSTRACT 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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    ABSTRACT: CD40 is expressed on various immune cells, including macrophages and micro- glia.Aberrant expression of CD40 is asso- ciated with autoimmune inflammatory dis- eases such as multiple sclerosis and rheumatoid arthritis. Interaction of Toll- like receptor-4 (TLR4) with the Gram- negative bacteria endotoxin lipopolysac- charide (LPS) results in the induction of an array of immune response genes. In this study, we describe that LPS is a strong inducer of CD40 expression in macrophages and microglia, which oc- curs at the transcriptional level and in- volves the activation of the transcription factors nuclear factor-B (NF-B) and sig- nal transducer and activator of transcrip- tion 1 (STAT-1). LPS-induced CD40 ex- pression involves the endogenous production of the cytokine interferon- beta (IFN-), which contributes to CD40 expression by the activation of STAT-1. Blocking IFN--induced activation of STAT-1 by IFN--neutralizing antibody reduces LPS-induced CD40 gene expres- sion. Furthermore, LPS induces acetyla- tion and phosphorylation of histones H3 and H4 and the recruitment of NF-B, STAT-1, and RNA polymerase II on the CD40 promoter in vivo in a time-depen- dent manner, all events important for CD40 gene transcription. These results indicate that both LPS-induced NF-B activation and endogenous production of IFN- that subsequently induces STAT-1 activation play critical roles in the tran- scriptional activation of the CD40 gene by LPS. (Blood. 2005;106:3114-3122)


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