Macdougall, Thomas Hugh James; (1999) Interactions between dendritic cells and HIV-1. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

HIV-1 infection results in progressive damage to the immune system, usually resulting in the eventual death of the individual due to opportunistic infections. Experiments by other researchers have demonstrated that there is a defect in CD4⁺ T-cell responses to antigen, and that some of this effect is mediated by the gp120 component of the virus. Dendritic cells (DC), which are professional antigen presenting cells, have unique ability to stimulate naive T cells as well as initiate secondary responses. In infected patients they have been shown to be defective for T-cell stimulation, and to be present in reduced numbers, possibly due to injury by HIV-1 infection. This PhD has examined the hypothesis that gp120 interaction with DC may be partially responsible for the functional defects seen in DC; and that HIV-1 infection of the DC themselves is an important cause of DC injury. Using both a macrophage tropic (SF162), and a T-cell line tropic (SF2) strain of HIV-1 as sources for the gp120 gene, human cell lines expressing rgp120 from both strains have been produced. This rgp120 has been purified extensively using a combination of affinity purification and ion-exchange chromatography to give a supply of pure gpl20. Both rgp120s were shown to inhibit the ability of DC to stimulate CD4⁺ and CD8⁺ cells significantly, in autologous and allogeneic T cell responses, at physiologically relevant concentrations. This inhibitory effect was mediated predominantly at the DC level, as opposed to the T-cell level, and preliminary investigations have suggested that gp120 induces signalling in the DC, indicating a possible effect or route. Analysis of the replication kinetics of HIV-1 within DC showed that a variety of both macrophage tropic and T-cell line tropic isolates can infect both immature and mature DC, albeit to differing extents. Infection had no apparent effect on the cell surface phenotype, morphology, or viability of DC. The presence of activated T cells, which have previously been shown to enhance the replication of HIV-1 within macrophages significantly, was shown to have an effect on HIV-1 replication in DC, which varied depending on the isolate used and the maturation state of the DC.

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