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

Zidovudine (AZT) has been shown to reduce maternal-fetal transmission of HTV-1 by more than two-thirds in a variety of clinical settings. Ho wever, the mechanism of action of AZT in this setting is unclear. Supp ression of vertical transmission has occurred in the absence of ail im pact on maternal plasma viremia and no lower threshold of viral load f or such transmission has been identified. We hypothesized that augment ation 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 co mbination of physiologic concentrations of progesterone (10(-7) to 10( -6) M) and low-dose AZT (10(-8) to 10(-9) M) produced markedly synergi stic inhibition of HIV-1 replication within acutely infected monocytic cell lines (U937), and additive inhibition of HIV-1 growth within chr onically infected monocytic cells (U1) and primary placental macrophag es (Hofbauer cells). Anti-HIV effects were not seen with another pregn ancy steroid hormone, estrogen. In terms of possible mechanisms of act ion for progesterone, we demonstrated that it incompletely suppressed fat 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 proges terone/androgen/glucocorticoid response elements within the HIV-1 LTR, previously shown by our group to be involved in glucocorticoid-mediat ed suppression of LTR-driven transcription. It is likely that progeste rone suppresses LTR-driven gene expression through a nontranscriptiona l mechanism, and augments the efficacy of AZT through enhancement of i ts phosphorylation.