The central hypothesis of this proposal is that high HIV-1 load is the critical risk factor which influences vertical transmission, and that specific viral phenotypes and genotypes, autologous neutralizing antibody, and cell-cell interactions are important determinants of viral burden.
The specific aims are:
Specific Aim 1 : To identify virologic markers predictive of mother-to-infant transmission. These studies will include quantitation of maternal HIV-1 load using quantitative PCR of plasma RNA, plasma intravirion DNA and proviral DNA, quantitative plasma and PBMC culture, and ICD p24 antigen. The role of syncytium inducing/nonsyncytium inducing phenotype, macrophage- versus T-cell tropism, and phenotypic and genotypic antiretroviral resistance in maternal-infant transmission will also be evaluated.
Specific Aim 2 : To determine the role of autologous neutralizing antibody in mother-to-infant transmission. For these studies, maternal sera will be evaluated for their ability to neutralize autologous HIV-1 isolates, and correlated with maternal virus load and maternal- infant transmission. Questions to be answered will include: a) Does the presence of autologous neutralizing antibody prevent mother-to-infant transmission? b) Does autologous neutralizing antibody differentially affect early versus late maternal-infant transmission? and c) Does zidovudine treatment decrease mother-to-infant transmission in the presence and absence of autologous neutralizing antibody? d) Do monoclonal antibodies directed against gp120 neutralize viral strains that escaped neutralization by a transmitting mother? Specific Aim 3: To identify the importance of enhanced HlV-1 replication in macrophages during macrophage- endothelial cell contact on mother-to-infant transmission, and to develop potential therapeutic approaches to decrease viral replication and block vertical transmission. The hypothesis of this research is that the upregulation of HIV-1 replication in macrophages at the critical point of egress at the vascular endothelium leads to an increase in the overall viral load to which an infant is exposed, and, thus, increases the risk of mother-to-infant transmission. In the experiments proposed, we will examine HIV-1 isolates from transmitting and nontransmitting mothers to determine their relative ability to be upregulated in macrophage- endothelial cell cocultures. Additionally, we will examine the ability of monoclonal antibodies directed against endothelial and leukocyte adhesion molecules, synthetic peptides, antisense oligonucleotides, cytokines and anti-adhesion pharmacologic agents for their ability to block increased HlV-1 replication in macrophage-endothelial cell cultures. The goal of the proposed research is to develop a better understanding of the factors which mediate mother-to-infant HIV-i transmission, and to develop novel strategies which can be used in conjunction with antiretrovirals to prevent vertical transmission.
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