Extensive viral diversity is a key feature of HIV infection. Within an individual, HIV exists as a population of related yet distinct viral variants or subpopulations across body compartments. Characterizing these variants and the evolutionary (mutation, recombination, selection) and population processes (bottlenecks) that generated them is key to understand HIV infection, transmission and pathogenesis. But within host HIV dynamics is complex and difficult to study in human subjects due to sampling constraints and the diverse genetic backgrounds of different hosts. Therefore, animal models that can mimic human HIV evolution under more controlled conditions would provide an ideal tool to better understand HIV evolution, especially at early stages of infection. Humanized mice have a functional human immune system and can recapitulate most key aspects of HIV infection and pathogenesis in humans. Moreover, they are cost-efficient, can be replicated in large numbers and provide a genetically homogeneous ‘host’ background across replicates. These unique characteristics make humanized mice a potentially exceptional model to study the evolutionary dynamics of HIV.
In this proposal, we will use two humanized mouse models (RAG-hu and NSG) to test for HIV evolutionary dynamics at early infection. Coupling this novel experimental model with high-throughput sequencing and state-of-the-art methods of genetic analysis, we will assess if a) HIV-1 subtype B populations in humanized mice experience a bottleneck during sexual transmission; b) if HIV-1 evolution is driven by genetic drift and/or natural selection at early infection; c) how HIV-1 genetic diversity is temporally and spatially structured across body compartments. We hypothesize that these two humanized mice models can replicate human HIV-1 dynamics at the intra-host level. Insights from this proposal may provide a powerful and innovative strategy to study HIV evolution and help to characterize the evolutionary dynamics of HIV at early infection. Ultimately, such information will increase our understanding of HIV pathogenesis and could lead to the development of novel strategies to prevent and eradicate AIDS.