Master of Science
Microbiology and Immunology
Dr. Eric Arts
Dr. Carole Creuzenet
Although several studies have determined key differences in envelope motifs between TF and chronic HIV-1, it is still not known what the overall glycosylation profile is that is selected for in a transmission event, as well as what contributes to this selection. Using a bottom-up approach of modifying specific viruses, determining their transmission fitness in an ex vivo tissue explant assay, and determining their glycan content, we have laid the basis for determining the overall glycan structure which is selected for in TF HIV-1. Preliminarily, we have shown that C-type lectins represent a stringent barrier to transmission and have several modified viruses to be tested to determine a glycan profile that is most similar to TF HIV-1. Knowledge of the overall glycan motifs which are selected for in a transmission event provides the means necessary to target TF in a prophylactic therapy.
Summary for Lay Audience
HIV-1 is a genetically diverse virus which produces thousands of different variants during infection in a host. When male-to-female transmission occurs, out of the thousands of variants present, a single virus is able to establish infection in 80% of cases. This virus is called the transmitted/founder virus (TF). As someone is infected with HIV-1 for an extended period of time, the viral population present in the host is distinct compared to the virus which first transmitted, the TF. For example, they differ from one another through a protein on their surface known as gp120. These proteins act as spikes which bind to cells to infect them. They contain sugars on their surface which function to shield the virus from the immune system. TF viruses have been shown to contain less sugars on the surface of their gp120 proteins compared to chronic viruses, but it has not been shown why this is the case. The female genital tract contains many defense mechanisms which function to prevent HIV-1 from infecting its host. One of these defense mechanisms are sugar-binding proteins known as C-type lectins. These proteins have been shown to bind to HIV-1 and signal other cells to destroy it. We propose that HIV-1 TF viruses with less sugar on their surface, are able to escape C-type lectins and are thus better able to infect the host. In this thesis, we looked to determine what the best sugar content for transmission was by modifying the viral sequence, growing viruses in the presence of sugar content inhibitors, and cleaving the sugars off of the viruses with enzymes. The original viruses transmission fitness was tested using a tissue model developed to mimic a transmission event. Further, an assay was optimized to measure binding strength of our viral gp120 proteins to C-type lectins. This will help determine if certain modified viruses are better able to avoid trapping by this defence mechanism. Overall, this lays the ground work by generating the modified viruses necessary to determine the sugar content of the TF virus. Future studies can build to develop therapies targeting the TF virus.
Meadows, Adam, "Encountering Lectins In The Recipient Mucosa: Implications Of N-linked Glycosylation On HIV-1 Transmission" (2019). Electronic Thesis and Dissertation Repository. 6720.
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