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Filling the gaps: Towards improved surveillance and monitoring of immunological status relevant to long term co-morbidities in HIV infection

Castley, Alison (2016) Filling the gaps: Towards improved surveillance and monitoring of immunological status relevant to long term co-morbidities in HIV infection. PhD thesis, Murdoch University.

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It is approaching 35 years since human immunodeficiency virus (HIV)-1 was first identified in Western Australia (WA) and 20 years since introducing highly active antiretroviral therapy (HAART) transforming HIV management, in the majority of cases, by maintaining ‘undetectable’ HIV-1 RNA and restoring CD4 T cell counts to healthy levels. Despite these advances patients are at increased risk of developing age-associated diseases. This thesis therefore investigates whether expanding laboratory approaches to incorporate aspects of the disease process, that are currently 'invisible' in clinical practice but may be prognostically important or which may inform treatment and prevention strategies at a population level, is warranted.

The following aims were addressed; 1) analysing determinants of HIV-1 RNA residual viraemia; 2) investigating monocyte activation during chronic HIV-1 infection and; 3) assessing HIV-1 diversity from large scale sequences throughout WA and Australia, including the collaboration and formation of the Australian Molecular Epidemiology Network (AMEN).

The main findings demonstrated HIV-1 residual viraemia was powerfully associated with the pre-treatment level of viraemia even after 10-15 years of starting HAART. Analysis of monocyte activation revealed multiple pathways involved in chronic immune activation responses to HIV-1, by altering CD16+ monocyte expression and elevated levels of sCD14 (previously associated with all-cause mortality), that were not corrected by HAART and therefore prognostically significant. In contrast, levels of other biomarkers (e.g. CXCL10 and sCD163) declined with HAART.

Investigations of HIV-1 genetic diversity within the WA cohort (n=1021) and the Australian cohort (n=4873) revealed new challenges for HIV-1 prevention due to significant increases in HIV-1 non-B-subtypes, consistent with an increasing impact of migration, while local transmissions were predominantly HIV-1 B-subtypes.

Overall, this thesis provides evidence for possible new approaches that may enhance HIV-1 laboratory practice that could aid clinical management, improve long-term health outcomes for those living with HIV-1 infection and guide effective preventative strategies.

Item Type: Thesis (PhD)
Murdoch Affiliation(s): School of Veterinary and Life Sciences
Supervisor(s): Nolan, David and Berry, Cassandra
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