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Title: Antibody effector functions critical to mucosal protection against HIV-1
Author: Cheeseman, Hannah Mary
ISNI:       0000 0004 7657 1512
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Human Immunodeficiency Virus-1 (HIV-1) is a retrovirus that was identified more than thirty years ago as the cause of Acquired Immunodeficiency Syndrome (AIDS). The only HIV-1 vaccine trial to demonstrate any potential, the Thai RV144 HIV-1 vaccine trial, was correlated with antibody-dependent cellular cytotoxicity (ADCC) mediated by non-neutralising antibodies (nnAb). This has led to speculation that ADCC and other antibody-dependent cellular effector functions might provide an important defence against mucosal acquisition of HIV-1 infection. However, the ability of antibody-dependent cellular effector mechanisms to impact on early mucosal transmission events is unknown and will depend on a variety of parameters including effector cell type, frequency, the class of Fc receptor (FcR) expressed, the number of FcR per cell and the glycosylation pattern of the induced antibodies. This project seeks to test the hypothesis that the protective effect of HIV-1 antibodies is likely dependent upon their functional activity in mucosal tissues, which may not be predicted by conventional neutralisation assays. To test this hypothesis, initial work was undertaken to characterise and compare the frequency and phenotype of IgG (CD16 [FcγRIII], CD32 [FcγRII] and CD64 [FcγRI]) and IgA (CD89 [FcαR]) receptor expression on effector cells within male and female genital mucosal tissue, colorectal tissue and whole blood. The frequency of FcR expression on CD14+ monocytic cells, myeloid dendritic cells and natural killer cells were similar across the three mucosal tissue compartments, but significantly lower when compared to the FcR expression profile of effector cells isolated from whole blood, with many cells negative for all FcRs. Subsequently, the activity of neutralising (nAb) and nnAb within the mucosal explant inhibition assay with penile glans, ectocervical and colorectal tissue was investigated. The results showed that, within the three mucosal tissues, none of the nnAb tested were efficient at preventing infection. Conversely, nAb demonstrated good levels of inhibition in all three mucosal tissue types. Finally, to determine whether a potential influx of effector cells from the periphery could impact on antiviral activity, the ability of nAb and nnAb to reduce HIV-1 infection in the presence of whole blood were assessed. Furthermore, the binding of these antibodies to HIV-1 infected cells was investigated. The data showed that nnAb were unable to reduce infection of CD4+ cells, although they showed some ability to reduce onward viral transmission. However, nAb were able to reduce the level of infection in this assay system. Antibody binding to infected cells did not correlate with reduction in HIV-1 infection. In summary, the combined data demonstrated that nnAb were insufficient at preventing HIV-1 transmission. Conversely, nAb were capable of reducing HIV-1 infection in all of the assay systems investigated, indicating that it is nAb that should be the primary focus of future vaccine discovery.
Supervisor: Shattock, Robin ; King, Deborah Sponsor: Duke Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral