<p>Breastfeeding from HIV-infected mothers is one of the major sources of pediatric HIV-1 infection; however, an intervention that promotes exclusive breastfeeding has significantly reduced vertical HIV transmission rates and infant mortality. The mechanisms underlying this phenomenon remain unknown; however, have been closely linked to high levels of innate immune factors in breast milk. Indeed, the level of several innate factors in breast milk correlate with protection and/or have direct anti-viral properties <em>in vitro.</em> The innate immune factor, soluble TLR2 (sTLR2) is found in high concentration in breast milk and has previously been investigated for its anti-bacterial properties; however, its anti-viral properties remain poorly understood. Thus, the research presented in this thesis extended our understanding of sTLR2 by characterizing the mechanisms by which sTLR2 inhibited HIV-induced inflammation and infection. Chapter 2 examined the predominant forms of sTLR2 in breast milk from different women, its cellular source, bioavailability and kinetics postpartum. Functionally, we confirmed sTLR2’s anti-bacterial properties and extended to show, for the first time, that sTLR2 directly inhibited HIV infection <em>in vitro.</em> Chapter 3 documented a potential mechanism of sTLR2’s direct inhibition of HIV infection <em>in vitro</em> and, investigated sTLR2 and TLR2 expression in HIV uninfected compared to HIV infected breast milk and breast milk cells, respectively. Chapter 4 investigated the role of TLR2’s recognition of novel HIV pathogen associated molecular patterns (PAMPs), and whether TLR2 expression increased HIV infection and integration. Taken together, we present novel anti-viral functions of sTLR2 by demonstrating that sTLR2 bound to specific HIV PAMPs, which led to significantly decreased HIV-induced inflammation, co-receptor expression, and HIV infection. Furthermore, we demonstrated, for the first time, that TLR2 recognizes specific HIV PAMPs, which led to significantly increased pro-inflammatory cytokine production, co-receptor expression and HIV infection. Thus, sTLR2 and TLR2 represent innate immune factors that might have preventative and therapeutic applications for both infants and adults in the future.<strong><br /> </strong></p> / Doctor of Philosophy (Medical Science)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/13312 |
| Date | 10 1900 |
| Creators | Henrick, Bethany M. |
| Contributors | Rosenthal, Kenneth L., Stampfli, Martin, Medical Sciences |
| Source Sets | McMaster University |
| Detected Language | English |
| Type | thesis |
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