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UBC Theses and Dissertations

A Caulobacter crescentus microbicide prevents vaginal infection with HIV-1 and HSV-2 in preclinical models Farr, Christina


Over 2 million people are infected with HIV each year. The majority of these infections occur in women residing in low-income countries, where their access to and control over preventative measures is often limited. This suggests that female-controlled prevention options for HIV-1 are urgently needed. Microbicides, which can be topically applied to the vaginal tract in advance of sexual activity to protect from HIV-1 infection, represent a promising female-controlled prevention option. We have investigated the development of an HIV-1 specific microbicide using the non-pathogenic, freshwater bacterium Caulobacter crescentus. C. crescentus contains a Surface or S-layer that is easily modified for high-density display of recombinant proteins. We have developed 18 recombinant C. crescentus that display anti-HIV proteins, including decoy receptors and ligands, anti-viral lectins and fusion inhibitors, that can prevent various steps of the HIV-1 attachment and entry process. In vitro testing with these recombinant C. crescentus indicated that 15 were able to provide substantial protection from HIV-1 infection. Studies with immune-competent mice demonstrated that application of C. crescentus to the vaginal tract does not induce the production of inflammatory cytokines or recruitment of immune cells. To test for protection against HIV-1 in vivo we have combined the implantation of human fetal liver and thymus tissue with the intravenous injection of autologous CD34+ cells into NOD-scid IL2Rγnull mice to create humanized Bone Marrow-Liver-Thymus (BLT) mice and we have demonstrated that the peripheral blood of these mice contains human CD45+ cells, including CD4+ and CD8+ T cells, B cells, myeloid cells, and NK cells. Our data indicates that vaginal application of recombinant C. crescentus at the time of HIV-1JR-CSF infection provides protection from HIV-1 infection. Seven of the recombinant C. crescentus were predicted to also prevent infection with herpes simplex virus 2 (HSV-2). HSV-2 is a major co-morbidity for HIV-1 infection, contributing to a 2-4 fold increase in acquisition. Four recombinant C. crescentus provided significant protection from HSV-2 infection in vivo. Taken together this data suggests that a C. crescentus based microbicide could be a safe and effective method to prevent infection with HIV-1 and HSV-2, having considerable impact on public health.

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