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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI032319-04
Application #
2067191
Study Section
AIDS and Related Research Study Section 4 (ARRD)
Project Start
1991-09-30
Project End
1996-06-30
Budget Start
1994-08-01
Budget End
1996-06-30
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Rochester
Department
Obstetrics & Gynecology
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Polliotti, B M; Gnall-Sazenski, S; Laughlin, T S et al. (2002) Inhibitory effects of human chorionic gonadotropin (hCG) preparations on HIV infection of human placenta in vitro. Placenta 23 Suppl A:S102-6
Sheikh, A U; Polliotti, B M; Miller, R K (2000) Human immunodeficiency virus infection: in situ polymerase chain reaction localization in human placentas after in utero and in vitro infection. Am J Obstet Gynecol 182:207-13
Sheikh, A U; Polliotti, B M; Miller, R K (2000) In situ PCR detection of HIV expression in the human placenta. Methods Mol Biol 137:75-86
Miller, R K; Polliotti, B M; Laughlin, T et al. (2000) Role of the placenta in fetal HIV infection. Teratology 61:391-4
Plessinger, M A; Miller, R K (1999) Effects of zidovudine (AZT) and dideoxyinosine (ddI) on human trophoblast cells. Reprod Toxicol 13:537-46
Boal, J H; Plessinger, M A; van den Reydt, C et al. (1997) Pharmacokinetic and toxicity studies of AZT (zidovudine) following perfusion of human term placenta for 14 hours. Toxicol Appl Pharmacol 143:13-21
Plessinger, M A; Boal, J H; Miller, R K (1997) Human placenta does not Reduce AZT (zidovudine) to 3'-amino-3'-deoxythymidine. Proc Soc Exp Biol Med 215:243-7
Genbacev, O; White, T E; Gavin, C E et al. (1993) Human trophoblast cultures: models for implantation and peri-implantation toxicology. Reprod Toxicol 7 Suppl 1:75-94