This application is aimed at investigating the importance of peripartum exposure of the fetus/neonate to HIV-infected maternal genital tract secretions as a mechanism for vertical transmission, and the importance of the genital tract immune response in protecting the infant from vertical transmission of HIV-1. To achieve their goals, the applicants propose the following hypotheses: (1) the rate of vertical transmission varies directly with the amount of virus present in the genital tract; (2) the amount of virus in the genital tract varies directly with the amount of virus in the peripheral blood, the amount of genital tract inflammation and cervical ectopy, and varies inversely with the maternal CD4 count; (3) the presence and titer of HIV-specific antibodies in the cervical lavage fluid varies inversely with the rate of transmission. In addition, the applicants propose to conduct preliminary studies on several additional issues: (i) whether the risk of transmission is related to the presence of obstetrical co-factors including duration of rupture of membranes; (ii) whether the presence of virus in the genital tract is independent of AZT use but quantitatively reduces viral burden in the genital tract; (iii) whether there is heterogeneity between peripheral blood and genital HIV isolates; (iv) whether infant viral isolates will be most closely linked to genital tract isolates; (v) whether AZT resistant isolates in the genital tract are more likely to be transmitted than sensitive isolates; and (vi) whether women taking AZT prior to pregnancy are more likely to have resistant isolates in the genital tract than women who begin AZT during pregnancy. This application several Specific Aims, namely: (1) To assess the relationship between lower genital tract virus (detected by DNA-PCR and culture performed on cervico-vaginal lavage(CVL) specimens) and vertical transmission; (2) to determine the relationships between clinical factors that are potentially modifiable or that are important predictors of vertical transmission, and the presence and amount of virus in the lower genital tract; and (3) to assess the impact of local, lower genital tract immunity on transmission. The study population for the proposed work will consist of women enrolled in WITS who have appropriate CVL specimens obtained. Appropriate specimens for PCR and antibody testing are those that can be transported rapidly to a WITS- designated on-site laboratory and frozen within 4 hours. Specimens from participants at the Brigham and Women's site will also undergo immediate culture for HIV. CVL specimens are obtained from WITS participants at the time of enrollment, 34 weeks gestation, and 2 and 6 months postpartum. In addition, blood samples will be taken for PBMC HIV culture from the Brigham and Women's site participants. Clinical histories and physical exams, including gynecological examinations with culture for Candida and vaginal pathogens, will be part of the WITS data routinely obtained. Specimens from 100-150 women/per year are expected for the PCR and antibody determination along with 100 specimens from the WITS repository. Specimens from approximately 20 women/per year will be available for culture. DNA-PCR samples from transmitting mother-infant pairs will be analyzed by heteroduplex mobility analysis and sequencing. The applicants estimate taht 2-3 paired samples/per year will be available for determination of ZDV resistance.
| Tuomala, Ruth E; O'Driscoll, Peter T; Bremer, James W et al. (2003) Cell-associated genital tract virus and vertical transmission of human immunodeficiency virus type 1 in antiretroviral-experienced women. J Infect Dis 187:375-84 |
