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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS063897-04
Application #
8213743
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
2009-02-15
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
4
Fiscal Year
2012
Total Cost
$619,844
Indirect Cost
$154,748
Name
University of Florida
Department
Pathology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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
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
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
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
Nowlin, Brian T; Burdo, Tricia H; Midkiff, Cecily C et al. (2015) SIV encephalitis lesions are composed of CD163(+) macrophages present in the central nervous system during early SIV infection and SIV-positive macrophages recruited terminally with AIDS. Am J Pathol 185:1649-65
Lamers, Susanna L; Nolan, David J; Rife, Brittany D et al. (2015) Tracking the Emergence of Host-Specific Simian Immunodeficiency Virus env and nef Populations Reveals nef Early Adaptation and Convergent Evolution in Brain of Naturally Progressing Rhesus Macaques. J Virol 89:8484-96
Fogel, Gary B; Lamers, Susanna L; Liu, Enoch S et al. (2015) Identification of dual-tropic HIV-1 using evolved neural networks. Biosystems 137:12-9
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
Strickland, Samantha L; Rife, Brittany D; Lamers, Susanna L et al. (2014) Spatiotemporal dynamics of simian immunodeficiency virus brain infection in CD8+ lymphocyte-depleted rhesus macaques with neuroAIDS. J Gen Virol 95:2784-95
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

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