Molecular Mechanisms of HIV-1 Infection in Neonatal Target Cells

Abstract

HIV-1-infected neonates and infants have a higher viral load and progress to symptomatic AIDS more rapidly than their own infected mothers, as well as other infected adults, with differences in clinical manifestations, recurrent bacterial infections and CNS disorders. Two major reasons have been attributed to this differential HIV pathogenesis and disease; the relative immaturity of the neonate’s immune system and it’s inability to contain the highly replicating and mutating HIV-1, and the more efficient replication of HIV-1 in neonatal cells than in adult target cells. In this context, it has been demonstrated that HIV-1 replicates more efficiently in neonatal (cord) blood monocytes/macrophages and T lymphocytes – including naive and memory T lymphocytes – compared with adult blood cells. We have also determined the mechanisms of the differential HIV-1 replication in cord versus adult blood monocytes/macrophages and T lymphocytes (naive and memory), finding that it was influenced at the level of HIV-1 gene expression. The increased HIV-1 gene expression in neonatal versus adult target cells was regulated by differential expression of host factors, transcription factors (NF-κB, E2F, HAT-1, TFIIE, Cdk9 and Cyclin T1), signal transducers (STAT3 and STAT5A) and cytokines (IL-1β, IL-6 and IL-10). We also showed that nuclear extracts from cord cells interacted with HIV-1 long terminal repeat cis-acting sequences, including NF-κB, NFAT, AP1 and NF-IL6, to a greater extent when compared with adult peripheral blood mononuclear cell nuclear extracts. Additionally, shRNA of retroviral origin for STAT3 and IL-6 downregulated both their own gene expression as well as that of HIV-1, indicating that these factors influenced the differential expression of HIV-1 genes in cord cells compared with adult cells. In addition, HIV-1 integration plays an important role in differential HIV-1 replication and gene expression in neonatal versus adult cells by integrating into more actively transcribed genes in neonates compared with adults. We characterized 468 HIV-1 integration sites within cord and adult blood T lymphocytes and monocytes/macrophages, including genes coding for cellular components, and those involved with maintenance of the intracellular environment, enzyme regulation, cellular metabolism, catalytic activity and cation transport, as well as several potential transcription factor binding sites at the sites of integration. Additionally, the genes at the integration sites, transcription factors and transcription binding sites were expressed at higher levels in cord than adult target cells. In summary, the increased HIV-1 gene expression and replication in neonatal target cells due to differential expression of host factors all contribute to an increased viral load and faster disease progression in neonates and infants when compared with similar situations in adult patients. Based on these findings, it may be possible to identify new viral and host targets for use in developing strategies for the treatment and prevention of HIV-1.