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.
|Rife Magalis, Brittany; Nolan, David J; Autissier, Patrick et al. (2017) Insights into the Impact of CD8+ Immune Modulation on Human Immunodeficiency Virus Evolutionary Dynamics in Distinct Anatomical Compartments by Using Simian Immunodeficiency Virus-Infected Macaque Models of AIDS Progression. J Virol 91:|
|Mallard, Jaclyn; Papazian, Emily; Soulas, Caroline et al. (2017) A method for obtaining simian immunodeficiency virus RNA sequences from laser capture microdissected and immune captured CD68+ and CD163+ macrophages from frozen tissue sections of bone marrow and brain. J Immunol Methods 442:59-63|
|Rose, Rebecca; Lamers, Susanna L; Nolan, David J et al. (2016) HIV Maintains an Evolving and Dispersed Population in Multiple Tissues during Suppressive Combined Antiretroviral Therapy in Individuals with Cancer. J Virol 90:8984-93|
|Rife, Brittany D; Nolan, David J; Lamers, Susanna L et al. (2016) Evolution of Neuroadaptation in the Periphery and Purifying Selection in the Brain Contribute to Compartmentalization of Simian Immunodeficiency Virus (SIV) in the Brains of Rhesus Macaques with SIV-Associated Encephalitis. J Virol 90:6112-6126|
|Lamers, Susanna L; Rose, Rebecca; Maidji, Ekaterina et al. (2016) HIV DNA Is Frequently Present within Pathologic Tissues Evaluated at Autopsy from Combined Antiretroviral Therapy-Treated Patients with Undetectable Viral Loads. J Virol 90:8968-83|
|Salemi, Marco; Rife, Brittany (2016) Phylogenetics and Phyloanatomy of HIV/SIV Intra-Host Compartments and Reservoirs: The Key Role of the Central Nervous System. Curr HIV Res 14:110-20|
|Lamers, Susanna L; Rose, Rebecca; Ndhlovu, Lishomwa C et al. (2016) The meningeal lymphatic system: a route for HIV brain migration? J Neurovirol 22:275-81|
|Lamers, Susanna L; Rose, Rebecca; Nolan, David J et al. (2016) HIV-1 Evolutionary Patterns Associated with Metastatic Kaposi's Sarcoma during AIDS. Sarcoma 2016:4510483|
|Lamers, Susanna L; Fogel, Gary B; Liu, Enoch S et al. (2016) On the Physicochemical and Structural Modifications Associated with HIV-1 Subtype B Tropism Transition. AIDS Res Hum Retroviruses 32:829-40|
|Rife, Brittany D; Nolan, David J; Lamers, Susanna L et al. (2016) Correction for Rife et al., Evolution of Neuroadaptation in the Periphery and Purifying Selection in the Brain Contribute to Compartmentalization of Simian Immunodeficiency Virus (SIV) in the Brains of Rhesus Macaques with SIV-Associated Encephalitis. J Virol 90:8947|
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