Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Microbiology and Immunology

Supervisor

Arts, Eric J.

2nd Supervisor

Prodger, Jessica L.

Co-Supervisor

Abstract

There is in vivo evidence that suggests the genetic diversity of HIV-1 subtypes influence heterosexual transmission efficiency. To recapitulate sexual transmission in vitro, blocks of genital tissue were exposed to mixtures of genetically different subtype viruses. Migrating immune cells were collected and co-cultured with a CD4+ T-cell line permissive to HIV infection (PM1) to measure dendritic cell virus transfer; HIV-exposed tissues were cultured separately. Next generation sequencing (NGS) of HIV-1 DNA was used to quantify relative infection rates of the various challenge viruses, and to assess fitness differences in infection of the tissue vs. migratory/T cell co-cultures. Our results suggest a HIV-1 subtype’s ability to replicate in susceptible T cells may be predictive of its ability to replicate in susceptible tissue-resident cell populations. However, this may not reflect the ability of a subtype to be transported out of the tissue for infection elsewhere in the body.

Summary for Lay Audience

Human Immunodeficiency Virus Type 1 (HIV-1) is the causative agent for AIDS. Since the start of the epidemic, HIV-1 has evolved rapidly and resulted in different subtypes that are genetically diverse from one another. These subtypes are what’s driving the number of new infections worldwide. Studies have shown that the genetic diversity of the different subtypes contribute to how fast someone will start to experience AIDS. In particular, HIV-1 subtype C results in individuals progressing to AIDS at a much slower rate compared to HIV-1 subtypes A, B, and D. Researchers have speculated that this slower disease progression may result in more opportunity for new infections due to the fact that these individuals will likely only seek treatment when they experience AIDS-like symptoms. This makes sense, as HIV-1 subtype C accounts for greater than 50% of infections worldwide when compared to the other subtypes. Although increased opportunity for infection would account for this larger prevalence, the transmission efficiency of the different subtypes may also play a role. To investigate the transmission efficiencies of the different subtypes, I infected explants of genital tissue with these different subtypes and measured their abilities to infect tissue and transmit to susceptible cells. In this study, I found that the ability of a virus to cause disease progression may be able to predict its ability to replicate in the tissue itself. However, this may not relate to the ability of a virus to transmit and infect other parts of the body. Future studies will need to include more viruses to help further discern the differences in transmission efficiencies between the HIV-1 subtypes.

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