Infection & Immunity / Currently, there are 38 million people living with human immunodeficiency virus (HIV-1)
worldwide and there were 680,000 HIV-related deaths in 2020 alone. The greatest cause of
mortality in people living with HIV (PLHIV) is infection with opportunistic pathogens such
as tuberculosis (TB), which accounts for one third of HIV-related deaths. PLHIV are 20
times more susceptible to TB and co-infection leads to significantly worsened outcomes in
terms of both diseases. Humanized mouse (hu-mouse) models, which possess human
immune cells for HIV to infect, have been useful for HIV research. Our aim is to create hu- mouse models of HIV, TB and co-infection to investigate disease progression, immune
responses, therapeutics, prevention and vaccination. NOD-Rag1null-IL2rgnull (NRG) mice are highly immunocompromised mice that are traditionally used to generate hu-mouse models. We are also developing NRG mice that are transgenic for human HLA-DR4 and HLA-A2 (DRAG-A2) and similar mice have been reported to have improved immune responses. NRG and DRAG-A2 mice were humanized with hematopoietic stem cells obtained from human umbilical cord blood. DRAG-A2 mice had significantly higher engraftment success rates (defined as the percentage of mice with >10% hCD45+) as well as higher overall CD45+ leukocyte, CD4+ T cell, CD19+ B cell and CD14+ monocyte reconstitution in the blood compared to huNRGs. huNRG mice were permissive to infection with JR-CSF or NL4.3-Bal-Env HIV-1 intravaginally or systemically. huDRAG-A2 mice were also infected intravaginally with NL4.3-Bal-Env HIV-1. huDRAG-A2 mice, but not huNRGs, produced HIV-specific IgG, indicating improved immune responses. huNRG mice were infected intranasally with mCherry-Erdman, YFP-H37Rv or H37Rv Mtb. huDRAG-A2 mice were also infected with H37Rv. Human immune cell involvement
and human-like granuloma formation was observed using flow cytometry and immunohistopathology. These findings show that the DRAG-A2 model may be optimal for
investigating HIV, TB and co-infection, which continue to be serious global health concerns. / Thesis / Master of Science (MSc) / Human immunodeficiency virus (HIV) and tuberculosis (TB) are infectious diseases that
affect millions of people worldwide every year. The greatest cause of death in people living
with HIV is co-infection with TB and HIV-positive individuals are much more likely to get
TB. Humanized mouse (hu-mouse) models possess human immune cells for HIV to infect
and are useful for studying HIV. Our goal is to create hu-mouse models of HIV, TB and
HIV/TB co-infection that will allow us to study how these diseases interact. We are
currently developing a traditional hu-mouse model (known as NRG), as well as an
improved next-generation model (known as DRAG-A2) with a more functional immune
system. Both models have been successfully infected with HIV or TB. Only DRAG-A2
mice were able to make antibodies against HIV. The improved DRAG-A2 model will
enable future studies on HIV, TB and co-infection, which continue to be understudied
global problems.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/27361 |
| Date | January 2022 |
| Creators | Lepard, Madeleine |
| Contributors | Gillgrass, Amy, Medical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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