Molecular mechanisms of HIV-1 infection: Entry, post-entry, and gene expression

In the last two decades, a great deal of progress has been made in understanding the molecular biology of HIV-1. However, critical aspects of HIV-1 pathogenesis in infected infants remain poorly understood. The majority of AIDS cases in infants occur as a result of vertical transmission of HIV-1, which occurs at a rate of more than 30%. Moreover, HIV-1 infected infants have a higher level of viremia and progress more rapidly to AIDS than infected adults. My hypothesis is that specific molecular and biological properties of HIV-1 and its differential interaction with hosts (neonates and adults) influence transmission, infection, and disease progression. The projects making up this dissertation investigate the molecular mechanisms of HIV-1 vertical transmission, HIV-1 infection in neonatal target cells at levels of entry and post-entry events, and gene expression, and feasibility studies of synthetic molecules that can be used as anti-HIV-1 agents. The env gp41, rev and Rev-responsive element (RRE) were characterized from HIV-1 isolates involved in perinatal transmission. The data indicate that open reading frames and functional domains of env gp41, rev and stem-loop structure of RRE were highly conserved in isolates from mothers and their infants. Furthermore, the mechanisms of HIV-1 infection in neonatal (cord) and adult mononuclear cells were investigated. It was found that HIV-1 replicated better in cord blood lymphocytes and monocytes/macrophages than its adult counterparts, with a more profound difference seen in monocytes/macrophages. This difference in HIV-1 replication kinetics was not influenced either at level of entry (CD4, CCR5 and CXCR4 expression) or early post-entry events (reverse transcription and translocation of HIV-1 DNA into the nucleus) but at the level of HIV-1 gene expression. The biological activity of Gal-Cer and its analogs, and glycolipid conjugates as anti-HIV-1 agents was evaluated. Gal-Cer and its analogs incorporated onto liposomes, and glycolipid conjugates inhibited HIV-1 infection by binding to gp120, suggesting that these agents can be developed as drug delivery vehicles to prevent HIV-1 infection. Results obtained from this dissertation provide new insights into the molecular mechanisms of HIV-1 vertical transmission and pediatric infection, which may be helpful in developing new preventive and therapeutic strategies.