Abstract & Commentary: Tetracycline and T-cell Activation
Tetracycline and T-cell Activation
Clinical efficacy may take toxic levels
By Dean L. Winslow, MD, FACP, FIDSA, Vice Chair, Department of Medicine, Chief, Division of AIDS Medicine, Santa Clara Valley (CA) Medical Center.
Synopsis: In cell culture, minocycline demonstrated a dose-dependent decrease in single-cycle HIV infection and decreased viral RNA expression. Minocycline also decreased reactivation from latency and modulated activation marker expression and cytokine secretion of CD4+ T-cells in response to activation.
Source: Szeto GL, et al. Minocycline attenuates HIV infection and reactivation by suppressing cellular activation in human CD4+ T cells. J Infect Dis. 2010;201:1132-1140.
CD4+ t cells were obtained from HIV-negative donors and HIV-positive patients receiving HAART with suppressed viremia. Using a single-cycle replication system and an X4 pseudovirus used to infect cells, minocycline, at concentrations from 0-50 ug/mL, demonstrated a dose-dependent reduction in the percentage of infected cells. T cells pretreated with minocycline, infected with HIV NL4-3, followed by activation with anti-CD3/CD28, yielded unchanged intracellular HIV DNA, but minocycline significantly reduced HIV RNA expression. In a cell-culture model of HIV latency, minocycline reduced the frequency of reactivation events by approximately 20%. In CD4+ T cells from HIV-infected patients with suppressed viremia on HAART pretreated with minocycline, reduced activation in response to anti-CD3/CD28 was observed as assessed by HIV gag RNA expression, although some degree of cytotoxicity was observed in vitro in the presence of the highest concentrations of minocycline. Dose-related suppression of expression of various cell-surface activation markers by minocycline was also demonstrated.
Commentary
This study reports a series of in vitro studies which demonstrate that minocycline suppresses HIV replication in CD4+ T cells, decreases response of CD4+ T cells to costimulation, blunts secretion of cytokines, and alters surface marker expression. In this paper, the authors speculate that the immunomodulatory and anti-HIV effects of minocycline might be useful clinically. I am skeptical about this since the concentrations of minocycline needed to see such clinically useful dramatic effects are close to the levels that would likely be toxic in vivo. (One weakness of the cell-culture experiments is that the authors used the very insensitive trypan blue-dye exclusion assay to assess cytoxicity instead of more sensitive studies that use tetrazolium dyes to assess cellular oxidative function.)
Despite the likelihood that the findings of this study may not have clinical application, I still found the results to be very interesting. Over the last 20 years or so, the immunomodulatory and anti-inflammatory effects of several protein-synthesis-inhibiting antibiotics have received increasing attention. For example, antibiotics such as clindamycin and linezolid have been shown to reduce toxin production by both staphylococci and streptococci, and are of benefit in animal models and in human toxic-shock syndrome. Similarly, macrolides, such as azithromycin, have been shown to have beneficial anti-inflammatory effects (independent of antimicrobial activity) in pneumonia when combined with either cell wall-active antibiotics or fluoroquinolones. Similarly, tetracyclines have been demonstrated to have anti-inflammatory activities and can even have some activity in non-infectious diseases such as rheumatoid arthritis. In HIV infection, where viral transcription is, to a large extent, driven by pro-inflammatory cytokines and CD4+ T cell activation, adjunctive therapy with other immunomodulatory agents more specific than tetracyclines, may still have a role some day in the treatment of HIV-infected patients.
CD4+ t cells were obtained from HIV-negative donors and HIV-positive patients receiving HAART with suppressed viremia. Using a single-cycle replication system and an X4 pseudovirus used to infect cells, minocycline, at concentrations from 0-50 ug/mL, demonstrated a dose-dependent reduction in the percentage of infected cells.Subscribe Now for Access
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