Despite the introduction of highly-active antiretroviral treatment (HAART), the proportion of newly HIV-1 infected patients developing HIV-associated dementia (HAD) is increasing. Currently, there is no effective therapy for HAD. Understanding the evolutionary factors driving the emergence of neurovirulent strains during disease progression is of pivotal importance to develop a realistic model of neuroAIDS. The objectives of the current proposal are to define viral evolutionary steps within the central nervous system (CNS) and select monocyte/macrophages from bone marrow, gut, lung and blood preceding and associated with the onset of neuropathogenesis. The Rhesus macaque model of neuroAIDS will be employed to study the evolution of the viral quasispecies during disease progression and to track SIV-infected macrophage subsets infiltrating the brain. 24 animals will be infected with a genetically-defined viral swarm. Peripheral blood and tissue samples will be collected over time and used for amplification of a 3.3kb fragment, including gp160, nef and 5'LTR, of the viral genome, as well as some full-length genomes from selected tissues. We will use laser-captured microscopy to isolate viral variants from specific productively infected macrophage in the brain at early and end stage disease. High-resolution phylogenetic, population genetics, and molecular clock algorithms (phylodynamics) will reveal genetic aspects of viral reservoirs linked to the onset of a neuropathogenic infection that have not yet been characterized because of ethical problems associated with tissue sampling in humans.
Specific Aim 1 will investigate the evolutionary dynamics of SIV in lymphoid and non- lymphoid tissues during the course of the infection via longitudinal PBMC/tissue macrophages sampling and brain biopsies of monkeys with and without CD8+ T-cell depletion;
Specific Aim 2 will identify macrophage subsets involved in brain entry and acting as potential viral reservoirs for brain infection. We will be able to identify tempo and mode of brain infection and evolutionary signatures leading to the emergence of infectious macrophage-tropic quasispecies that could be used to predict and monitor the disease. Equally important is the possibility to use the findings into developing drugs that target macrophage and viral quasispecies associated to neuropathogenesis. Overall, we will compile the most comprehensive database of longitudinal SIV sequences from a variety of tissues to date. The PI, although a new investigator without previous R01 funding, has significant experience in cutting-edge analysis of genetic data, and has assembled a unique and qualified interdisciplinary team to assist in the study.
This project on HIV-associated dementia examines the evolution of immunodeficiency viruses in various tissues involved in brain infection. A monkey model of neuroAIDS is used that mimics the course of HIV infection in humans. The result will be a description of the genetic basis for the onset of dementia in patients with AIDS leading the way to the development of new diagnostic and therapeutic tools.
|Lamers, Susanna L; Fogel, Gary B; Nolan, David J et al. (2014) HIV-associated neuropathogenesis: a systems biology perspective for modeling and therapy. Biosystems 119:53-61|
|Prosperi, Mattia C F; Yin, Li; Nolan, David J et al. (2013) Empirical validation of viral quasispecies assembly algorithms: state-of-the-art and challenges. Sci Rep 3:2837|
|Lamers, Susanna L; Nolan, David J; Strickland, Samantha L et al. (2013) Longitudinal analysis of intra-host simian immunodeficiency virus recombination in varied tissues of the rhesus macaque model for neuroAIDS. J Gen Virol 94:2469-79|
|Prosperi, Mattia C F; Salemi, Marco (2012) QuRe: software for viral quasispecies reconstruction from next-generation sequencing data. Bioinformatics 28:132-3|
|Strickland, Samantha L; Gray, Rebecca R; Lamers, Susanna L et al. (2012) Efficient transmission and persistence of low-frequency SIVmac251 variants in CD8-depleted rhesus macaques with different neuropathology. J Gen Virol 93:925-38|
|Ayres, Daniel L; Darling, Aaron; Zwickl, Derrick J et al. (2012) BEAGLE: an application programming interface and high-performance computing library for statistical phylogenetics. Syst Biol 61:170-3|
|Gray, Rebecca R; Tatem, Andrew J; Johnson, Judith A et al. (2011) Testing spatiotemporal hypothesis of bacterial evolution using methicillin-resistant Staphylococcus aureus ST239 genome-wide data within a bayesian framework. Mol Biol Evol 28:1593-603|
|Strickland, Samantha L; Gray, Rebecca R; Lamers, Susanna L et al. (2011) Significant genetic heterogeneity of the SIVmac251 viral swarm derived from different sources. AIDS Res Hum Retroviruses 27:1327-32|
|Lamers, Susanna L; Gray, Rebecca R; Salemi, Marco et al. (2011) HIV-1 phylogenetic analysis shows HIV-1 transits through the meninges to brain and peripheral tissues. Infect Genet Evol 11:31-7|
|Prosperi, Mattia C F; Ciccozzi, Massimo; Fanti, Iuri et al. (2011) A novel methodology for large-scale phylogeny partition. Nat Commun 2:321|
Showing the most recent 10 out of 14 publications