Pepstatin A inhibits the rapid turnover of chemokine receptors on trophoblast cells: Application on HIV therapy

Chemokine receptors (CCRs) have been identified as co-receptors for viruses , including HIV. To investigate the mechanism(s) of in utero HIV transmissi on, the kinetics of expression for CCR3, CXCR4 and CCR5 from 2 to 48 hours of culture with or without lymphokine stimulation was followed. Surface CCR appearance on TROPHO-1 cells follows a very rapid turnover rate during the first 8 hours of culture, while soluble CCR activity is present in the sup ernatants of trophoblast cell cultures in an inversely proportional manner as compared to membrane expression. In order to delineate the intracellular events involved in the expression and release of CCRs, the protease inhibi tor pepstatin A (PEP-A) was used. The presence of this agent abolished the surface expression of CCR3 and CXCR4 and considerably decreased CCR5, where as it diminished all soluble CCR activity. Thus CCR expression on trophobla st cells follows a time-dependent turnover and recycling to the cell membra ne as well as deliberation to the extracellular matrix through the endocyti c pathway. The fact that this mechanism can be inhibited by PEP-A renders t his agent an important therapeutic means against HIV transmission.