Minocycline Attenuates HIV Infection and Reactivation by Suppressing Cellular Activation in Human CD4⁺T Cells

Abstract

Treatment of human immunodeficiency virus (HIV) infection with highly active antiretroviral therapy (HAART) is effective but can be associated with toxic effects and is expensive. Other options may be useful for long-term therapy. The immunomodulatory antibiotic minocycline could be an effective, low-cost adjunctive treatment to HAART. Minocycline mediated a dose-dependent decrease in single-cycle CXCR4-tropic HIV infection and decreased viral RNA after infection of CD4+ T cells with HIV NL4-3. Reactivation from latency was also decreased in a primary CD4+ T cell-derived model and in resting CD4+ T cells from HIV-infected patients. Minocycline treatment resulted in significant changes in activation marker expression and inhibited proliferation and cytokine secretion of CD4+ T cells in response to activation. This study demonstrates that minocycline reduces HIV replication and reactivation and decreases CD4+ T cell activation. The anti-HIV effects of minocycline are mediated by altering the cellular environment rather than directly targeting virus, placing minocycline in the class of anticellular anti-HIV drugs.

Randomized trial of minocycline in the treatment of HIV-associated cognitive impairment

“…This may be secondary to the antiinflammatory properties offered by the drug. 28 Minocycline has been shown to have a neuroprotective effect in animal models for a variety of neurologic conditions. 13,29 In humans, the drug has been shown to have therapeutic benefit in clinical trials of multiple sclerosis and stroke.…”

rRNA Binding Sites and the Molecular Mechanism of Action of the Tetracyclines

“…However, the susceptibility of protozoa species which lack mitochondria (e.g., Trichomonas vaginalis, Giardia lamblia, Entamoeba histolytica) (7,66), as well as viral pathogens (Table 1), raises further questions about the exact molecular mechanism(s) of action of the tetracy-clines. In contrast to the proffered antiprotozoal activity via mitochondrial and endosymbiont rRNA binding, the antiviral activities of the tetracyclines have not been associated with rRNA binding (2,13,14,(68)(69)(70). Rather, the antiviral activity has been attributed in part to anti-inflammatory (4, 15), antiapoptotic (2), and neuroprotective (1) properties.…”

“…However, these studies do not agree on the exact target/binding site of the tetracyclines on the 16S rRNA (12). In addition, there is increasing evidence of other useful properties of the tetracyclines, such as their antiviral (2,13,14), anti-inflammatory (4,15), antiapoptotic (2), and neuroprotective activities (1), that are not explained by the 16S rRNA binding mechanism currently held for the antibacterial action of the tetracyclines.…”

Epigenetic Metabolite Acetate Inhibits Class I/II Histone Deacetylases, Promotes Histone Acetylation, and Increases HIV-1 Integration in CD4+T Cells

“…3B, the presence of acetate increases the expression of the early activation marker CD69 while surface expression of CD25 and CD154 are not affected. As CD25 and CD154 are, respectively, intermediate and late activation markers (70), it is possible that a stimulation period of 3 days is too brief to significantly modulate CD25 and CD154 among all the donors tested. Nonetheless, the increased expression of CD69 implies a positive effect of acetate on the activation profile of CD3/CD28-costimulated CD4 ϩ T cells.…”