Characterization of human immunodeficiency virus type 1 associated with and without vertical transmission

Abstract

Vertical transmission of human immunodeficiency virus type 1 (HIV-1) occurs at an estimated rate of 30% and accounts for 90% of all HIV-1 infections in children. Increased risk of vertical transmission correlates with advanced maternal disease status, low CD4+ lymphocyte count, and high viral load. However, the molecular mechanisms of vertical transmission are poorly understood, making it difficult to design effective strategies for prevention and treatment. Our hypothesis is that specific molecular and biological properties of HIV-1 are critical determinants of vertical transmission. We characterized the HIV-1 gag p17 matrix (MA) and nef genes associated with and without vertical transmission. In addition, we determined the effect of env gp120 from mother-infant pairs and from infected mothers who failed to transmit the virus to their infants (non-transmitting mothers) on HIV-1 replication, cellular tropism, cytopathic effects and co-receptor utilization. Our data indicate that the open reading frames and the functional domains of both the gag p17MA and nef genes were highly conserved in isolates from mothers and their infants. While there was no significant difference in the maintenance of open reading frames and the conservation of functional domains between isolates from transmitting and non-transmitting mothers, we found that the non-transmitting mothers' gag p17MA sequences were more homogenous compared with the transmitting mothers' sequences. In addition, we were able to associate several motifs in p17MA with either transmitting or non-transmitting status. To study the effect of gp120 on HIV-1 biology, we reciprocal inserted the gp120 from mother-infant pairs and non-transmitting mothers into a T-tropic infectious clone and found that the chimeras were unable to replicate in T-cell lines and did not form syncytia in MT-2 cells. Moreover, these chimeras used the CCR5 co-receptor for entry in the U373MAGI-CD4-CCR5 cell line. Both the mother-infant pairs' and the non-transmitting mothers' gp120 chimeras replicated well in primary peripheral blood lymphocytes (PBL) with no significant difference in replication kinetics. These results may be helpful in the understanding of the association of viral determinants and molecular mechanisms of vertical transmission, which may contribute towards the development of new strategies for treatment and prevention of HIV-1 infection in children.