Understanding of human immunodeificiency virus-1 entry inhibition and co-pathogenesis of human immunodeificiency virus-1 and Cryptococcus neoformans in variably polarized macrophages
Yi, Hyun Ah
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HIV/AIDS is now seen as a chronic disease in developed countries, whereas it still causes a great burden in developing countries. There have been global efforts to develop treatments and chemopreventive agents to prevent HIV-1 infection for the past 30 years. However, there is still very little known about the membrane fusion stage of HIV entry. The entry process is a promising target because of the possibility of blocking the virus before the infection is initiated. In chapter two of this dissertation, investigations were carried out to improve fusion inhibitors and simultaneously to uncover details of the fusion stage of viral entry. It was determined that the membrane fusion intermediate can be permanently trapped on the virus surface by a covalent moiety placed strategically within the sequence of membrane fusion peptide inhibitors. A factor leading to the great global burden caused by HIV/AIDS is HIV/AIDS-related opportunistic secondary infections. Cryptococcosis, caused by the fungal pathogen, Cryptococcus neoformans, is one of the most common opportunistic infections in HIV/AIDS patients. In chapters three and four of this dissertation, the molecular details of co-infection with HIV and C. neoformans were investigated. In chapter three, it was determined whether glucuronoxylomannan, a major component of the capsule of C. neoformans, inhibited or enhanced the HIV membrane fusion step. Studies were then performed to study the mechanism responsible for inhibition. In chapter four, the relationship between HIV-1 and Cryptococcus in human macrophages was studied in vitro. Macrophages are the critical innate immune barrier that both HIV and Cryptococcus encounter and can infect. Macrophages are hypothesized to undergo variable polarization during AIDS progression, and therefore, it was hypothesized that fungicidal activity will vary between these states and could be a determining factor in activation/dissemination of cryptococcosis in AIDS. In this chapter, variably polarized macrophages were studied for differential susceptibilities to phagocytosis and intracellular proliferation of C. neoformans.