Understanding natural mechanisms of protection against HIV infection and disease progression are key priorities for informing vaccine and microbicide design. The research presented in this thesis aimed to characterize mechanisms of defence in HIV-exposed seronegative (HESN) individuals, who naturally resist infection by HIV, and HIV-controllers, who are HIV-infected, but suppress viral replication in the absence of treatment.
Previous studies have linked resistance to HIV infection with low basal levels of gene transcription and reduced production of inflammatory mediators, suggesting an overall state of immune quiescence in HESN. Immune quiescence may also be protective in HIV-infected individuals, as immune activation drives disease progression. The central hypothesis of this thesis is that immune quiescence protects against HIV infection and disease progression by limiting the pool of activated target CD4+ T cells susceptible to HIV infection. This hypothesis was addressed by evaluating immune function in HESN from the Pumwani commercial sex worker cohort and HIV-controllers from the Manitoba elite controller cohort.
In HESN, immune quiescence was marked by low levels of circulating activated T cells and low levels of the proinflammatory mediators IL-1α and IL-8 in the cervical mucosa. Regulatory T cells (Tregs), which suppress T cell activation, were elevated in HESN, and may represent a driver of immune quiescence. Low T cell activation and elevated Tregs were associated with reduced cellular susceptibility to infection in vitro. These data suggest that immune quiescence protects against infection by limiting the activated target CD4+ T cell pool, in support of the central hypothesis.
HIV-controllers expressed low levels of the proinflammatory chemokines IP-10 and MCP-1 and low frequencies of activated T cells. These data demonstrate that immune quiescence is not only protective prior to exposure, but is also beneficial following infection. HIV-controllers also had elevated MIP-1α, reduced TGFβ and HIV-specific T cell proliferation responses, which contribute to protection by mechanisms other than immune quiescence.
Taken together, these data support a role for immune quiescence in protection from HIV infection and disease progression. Mechanisms of reducing inflammation and target cell activation should be considered during future HIV vaccine and microbicide development.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:MWU.1993/5201 |
| Date | 21 March 2012 |
| Creators | Card, Catherine M. |
| Contributors | Fowke, Keith (Medical Microbiology), Yao, XiaoJian (Medical Microbiology) Wylie, John (Medical Microbiology) Uzonna, Jude (Immunology) Soussi-Gounni, Abdel (Immunology) Lederman, Michael (Case Western Reserve University) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Detected Language | English |
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