This proposal describes a training program that includes both didactic study and a basic science research experience which will provide a solid foundation in viral pathogenesis both on a molecular and cellular level. the research proposed addresses the role of the placenta in vertical transmission of the human immunodeficiency virus (HIV). Pediatric infections are a rapidly growing component of the AIDS epidemic and vertical transmission accounts for more than 80% of the cases of pediatric AIDS. Intrauterine transmission is believed to be responsible for a significant proportion of cases, and a number of studies have shown that placentas of HIV-infected women are positive for the virus. Our hypothesis is that infection of the placenta plays a role in intrauterine transmission of HIV in vivo. Using various models for placental cells, we have determined that primary cells derive from term human placentae permit replication of five different strains of HIV-1 (IIIB, SF-2, 89.6, SF-162 and DV) with varying degrees of permissiveness. Infection of these cells has been confirmed using an ELISA for p24 viral antigen and an immunofluorescent assay for HIV antigens. Transformed trophoblastic cell lines have not been found to be infectable. Phase I of the program will build upon these in vitro models developed to study the characteristics and kinetics of HIV-1 replication in primary and transformed human placental cell cultures, and examine the role of placental cell differentiation in permissiveness for infection. We will characterize the viral entry pathway in placental cells and examine the effect of anti-HIV antibodies in neutralizing or possibly enhancing placental infection. This work will be carried out under the direction of Neal Nathanson, Professor and Chair of Microbiology. Jerome Strauss, Professor and Director, Division of Reproductive Research, will serve as a secondary basic science sponsor during this phase. In Phase II I will return to the Pediatric Infectious Diseases Division to address clinically relevant questions related to materno-fetal transmission. Studies will include the evaluation of HIV isolates obtained from mother-infant pairs to determine the role of placental cell tropism in vertical transmission and the examination of maternal serum specimens to determine the role of antibody neutralization or enhancement of placental cell infection, as well as continuing work on selected aspects of the studies initiated in Phase I. Although this program is designed to focus specifically on placental infection with HIV, the knowledge, skills and techniques developed in this training program have the potential applicable to many other viruses transmitted from mother to fetus.
| Kolson, D L; Collman, R; Hrin, R et al. (1994) Human immunodeficiency virus type 1 Tat activity in human neuronal cells: uptake and trans-activation. J Gen Virol 75 ( Pt 8):1927-34 |
