Minocycline, a safe, readily available, inexpensive, semisynthetic tetracycline derivative, has anti-inflammatory properties distinct from its antimicrobial activity. It has been used to alleviate CNS inflammation in several animal models of neurodegenerative diseases. Our laboratory demonstrated that minocycline prevented the development of SIN/-associated encephalitis in macaques. Minocycline-treated macaques had fewer lymphocytes and macrophages infiltrating the brain and lower levels of inflammatory markers. These findings prompted us to examine the effects of minocycline on the immune system of SIV-infected macaques, and in particular, the effects of minocycline on proliferation and activation of primary blood lymphocytes. Minocycline treatment in vitro inhibited T cell proliferation and activation, down-regulated CCR5 expression, reduced cell surface LFA-1 expression and reduced loss of CD45RA after SEB stimulation. In contrast, markers of lymphocyte homing, CCR7 and CD62L were not significantly affected. Lymphocytes from SIV-infected macaques treated with minocycline in vivo also had lower levels of the activation markers, CCR5 and LFA-1.

Given the profound effect of minocycline on proliferation and activation and the fact that HIV and SIV cause a profound dysregulation in the cell cycle, we examined the cell cycle progression of CD4+ T cells treated with minocycline. Minocycline-treated CD4+ T cells were arrested in the G0/G1 phase with significantly lower expression of proteins necessary for G0/G1 phase progression including c-Myc, cyclin D1, CDK4 and pRb. There also was a decrease in cell cycle progression of cells infected with HIV in vitro. Minocycline-treated CD4+ T cells had lower surface CD25 expression following antibody-induced stimulation as compared to untreated controls. However, culture with exogenous IL-2 increased surface CD25 expression. Minocycline may induce a heightened threshold for activation as its effect can be overcome by exogenous IL-2 administration. Activation-induced rises in intracellular calcium transients were suppressed by minocycline. The reduced levels of activation markers and proliferation may be caused by a decrease in intracellular calcium transients. Drugs that cause arrest at specific stages of the cell cycle may be beneficial in treating infectious agents such as HIV-1 that rely on host cell cycle progression for their life cycle and pathogenicity.