Molecular mechanisms of HIV-1 mother-to-child transmission and infection in neonatal target cells.
HIV-1 mother-to-child transmission (MTCT) occurs mainly at three stages, including prepartum, intrapartum and postpartum. Several maternal factors, including low CD4+ lymphocyte counts, high viral load, immune response, advanced disease status, smoking and abusing drugs have been implicated in an increased risk of HIV-1 MTCT. While use of antiretroviral therapy (ART) during pregnancy has significantly reduced the rate of MTCT, selective transmission of ART resistant mutants has been reported. Based on HIV-1 sequence comparison, the maternal HIV-1 minor genotypes with R5 phenotypes are predominantly transmitted to their infants and initially maintained in the infants with the same properties. Several HIV-1 structural, regulatory and accessory genes were highly conserved following MTCT. In addition, HIV-1 sequences from non-transmitting mothers are less heterogeneous compared with transmitting mothers, suggesting that a higher level of viral heterogeneity influences MTCT. Analysis of the immunologically relevant epitopes showed that variants evolved to escape the immune response that influenced HIV-1 MTCT. Several cytotoxic T-lymphocyte (CTL) epitopes were identified in various HIV-1 genes that were conserved in HIV-1 mother-infant sequences, suggesting a role in MTCT. We have shown that HIV-1 replicates more efficiently in neonatal T-lymphocytes and monocytes/macrophages compared with adult cells, and this differential replication is influenced at the level of HIV-1 gene expression, which was due to differential expression of host factors, including transcriptional activators, signal transducers and cytokines in neonatal than adult cells. In addition, HIV-1 integration occurs in more actively transcribed genes in neonatal compared with adult cells, which may influence HIV-1 gene expression. The increased HIV-1 gene expression and replication in neonatal target cells contribute to a higher viral load and more rapid disease progression in neonates/infants than adults. These findings may identify targets, viral and host, for developing strategies for HIV-1 prevention and treatment.
Ahmad
Nafees
N
Department of Immunobiology, College of Medicine, University of Arizona, Tucson, AZ, United States. nafees@u.arizona.edu
D000939:Epitopes / Q000276:immunology; D005260:Female; D015658:HIV Infections / Q000635:transmission* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000821:virology; D015728:Receptors, HIV / Q000276:immunology; D019966:Substance-Related Disorders / Q000150:complications
D000939:Epitopes; D015728:Receptors, HIV