Interaction of pregnancy steroid hormones and zidovudine in inhibition of HIV type 1 replication in monocytoid and placental Hofbauer cells: implications for the prevention of maternal-fetal transmission of HIV.

Abstract

Zidovudine (AZT) has been shown to reduce maternal-fetal transmission of HIV-1 by more than two-thirds in a variety of clinical settings. However, the mechanism of action of AZT in this setting is unclear. Suppression of vertical transmission has occurred in the absence of an impact on maternal plasma viremia and no lower threshold of viral load for such transmission has been identified. We hypothesized that augmentation of the anti-HIV effect of AZT may occur locally, at the maternal-fetal interface. We report that the pregnancy hormone progesterone at broad concentrations has little effect on acute HIV-1 infection of a monocytic cell line or primary peripheral blood cells. However, the combination of physiologic concentrations of progesterone (10[-7] to 10[-6] M) and low-dose AZT (10[-8] to 10[-9] M) produced markedly synergistic inhibition of HIV-1 replication within acutely infected monocytic cell lines (U937), and additive inhibition of HIV-1 growth within chronically infected monocytic cells (U1) and primary placental macrophages (Hofbauer cells). Anti-HIV effects were not seen with another pregnancy steroid hormone, estrogen. In terms of possible mechanisms of action for progesterone, we demonstrated that it incompletely suppressed tat activation of long terminal repeat (LTR)-driven gene expression in monocytic cells. However, the progesterone-mediated suppession of tat activation was not affected by mutation of the three consensus progesterone/androgen/glucocorticoid response elements within the HIV-1 LTR, previously shown by our group to be involved in glucocorticoid-mediated suppression of LTR-driven transcription. It is likely that progesterone suppresses LTR-driven gene expression through a nontranscriptional mechanism, and augments the efficacy of AZT through enhancement of its phosphorylation.