Anti-HIV therapy [initially, dideoxyadenosine (DDI) , combination DDI and zidovudine (AZT), and possibly TAT inhibitors] will be investigated in the human placenta in vitro from 6-15 weeks of gestation and at term (38-40 weeks). These studies will address the issues of transplacental passage of these therapies, as well as their metabolism by the human placenta and the toxicity of these agents on the placenta itself. Multiple approaches will be undertaken to determine the kinetic and toxic responses: 1) Normal Human Placentas (HIV-Negative): Two technics will be used to study metabolism, transfer, cellular distribution, and toxicity: slice studies and dual lobular placental perfusion. Slice studies will compare placentas from early and term pregnancies for differences in tissue binding/incorporation, metabolism, cellular distribution, and toxic effects on the trophoblast. Dual perfusion studies will utilize term tissue to establish the bidirectional transfer of DDI from mother to fetus and from fetus to mother at therapeutic blood levels and potentially toxic blood levels. Since the perfusions can be performed for periods of 24 hrs, we will be able to evaluate whether DDI has any direct toxic effect on the placenta, especially since we have been able to demonstrate cell division occurring under these perfusion conditions. 2) Intercurrent Disease Placentae: Placentas from intrauterine growth retarded (IUGR) pregnancies will also be evaluated. It is recognized that IUGR does not necessarily have a common mechanism of origin, but such studies may approximate compromised pregnancies associated with HIV positive women. Similar studies as described above, for the perfusion studies, will be performed to study compromised placentas and their differential ability to alter the transfer/metabolism of DDI. 3) Implantation Model: This laboratory has recently developed a novel culture technic for trophoblast in three-dimension and functioning human endometrium from single cells. Such cultures provide the opportunity for studying how the trophoblast, the human endometrium, and the """"""""implantation process"""""""" are affected by the drugs. Such studies would provide the opportunity to determine how anti-HIV drugs may adversely affect the developmental process via adversely affecting the placenta and/or endometrium. Future proposed studies would examine new anti-HIV therapy, e.g., TAT inhibitors and immunoglobulins, as these agents become clinically more relevant.
