Addressing and leveraging within- and between-host HIV genetic diversity towards ending the HIV pandemic

Globally, 37.6 million people are living with HIV, and an estimated 1.5 million new infections occur annually. While combination antiretroviral therapies have significantly reduced HIV related morbidity and mortality, and also reduce transmission risk, ending the pandemic will require an effective vaccine to prevent new infections, and a strategy to cure HIV for those already living with the virus. These dual goals however are still a long way off. One of the biggest challenges facing both HIV vaccine and cure development is HIV's extensive genetic diversity. At the same time however, the detailed study of both individual- and population-level HIV diversity can yield key biological insights that can help inform HIV vaccine and curative approaches. This thesis encompasses three original research chapters united under this theme. The first original research chapter of this thesis identifies mutational immune escape pathways in HIV subtypes A1 and D, two understudied subtypes that co-circulate in Uganda. It then goes on to formally compare escape pathways between HIV subtypes and characterize the mechanisms whereby they arise. This research was among the first to systematically explore the influence of viral genetic context on HIV diversity and identify constrained viral sites that may represent useful vaccine targets for these subtypes. The second original research chapter transitions to HIV cure research by highlighting the challenges imposed by intra- and inter-individual HIV diversity to the application of a novel molecular assay for HIV reservoir quantification. The third and final original research chapter describes the genetic composition of HIV sequences that persist in the body despite long-term antiretroviral therapy. Specifically, this study leverages information from HIV's within-host evolutionary history prior to therapy to estimate how long a given HIV sequence has been persisting in the body, revealing that the longest-lived HIV sequences are ones that harbour major genomic defects. While HIV diversity poses an enormous challenge to vaccine and cure development, results illuminate how it can also be harnessed to gain novel insights into HIV biology towards achieving these goals