Role of human immunodeficiency virus type 1 accessory genes in mother-infant transmission

Abstract

The majority of AIDS cases in children occur as a result of perinatal transmission of HIV-1 at an estimated rate of 30%. However, the molecular mechanisms and viral determinants associated with perinatal transmission are not known, thus making it difficult to develop strategies for prevention and treatment of HIV-1 infection. In this study, we have investigated the role of HIV-1 accessory genes vif, vpr and vpu in maternal-fetal transmission and the kinetics of HIV-1 replication in neonatal blood mononuclear cells. While there was a high degree of conservation of vif, vpr and vpu open reading frames in mother-infant pairs' isolates, the non-transmitting mothers' showed a high frequency of defective vif and vpr open reading frames. The functional domains required for Vif, Vpr and Vpu activity were highly conserved in sequences from transmitting mothers and their infants, but were found to exhibit defects, length polymorphism and substitutions in the conserved motifs of non-transmitting mothers' isolates. There was a low degree of heterogeneity in vif and vpr sequences from transmitting mothers and their infants and non-transmitting mothers. However the non-transmitting mother sequences were less heterogeneous than transmitting mother sequences. The vpu sequences from transmitting mothers and their infants were more heterogeneous than vif and vpr sequences. Phylogenetic analysis of vif, vpr and vpu sequences revealed distinct clusters for each mother-infant pair and non-transmitting mother, indicating that the sequences from same individual or linked individuals were more closer than unrelated individuals. Furthermore, we observed that HIV-1 replicates more efficiently in immature blood lymphocytes and monocytes/macrophages cells compared to mature blood cells, suggesting that increased susceptibility of neonatal cells to productive infection could result in rapid progression to AIDS in children. In addition, there was a difference in the susceptibility of neonatal and adult blood monocytes/macrophages to primary HIV-1 isolates. Taken together, these findings suggest that accessory genes vif, vpr and vpu may play an essential role in HIV-1 transmission from mother to infants and susceptibility of neonatal monocytes/macrophages may be critical for establishing productive infection. These findings may be helpful in the developing better strategies for prevention and treatment of HIV-1 infection in children.