title: Spatiotemporal dynamics of simian immunodeficiency virus brain infection in CD8+ lymphocyte-depleted rhesus macaques with neuroAIDS.
abstract: Despite the success of combined antiretroviral therapy in controlling viral replication in human immunodeficiency virus (HIV)-infected individuals, HIV-associated neurocognitive disorders, commonly referred to as neuroAIDS, remain a frequent and poorly understood complication. Infection of CD8(+) lymphocyte-depleted rhesus macaques with the SIVmac251 viral swarm is a well-established rapid disease model of neuroAIDS that has provided critical insight into HIV-1-associated neurocognitive disorder onset and progression. However, no studies so far have characterized in depth the relationship between intra-host viral evolution and pathogenesis in this model. Simian immunodeficiency virus (SIV) env gp120 sequences were obtained from six infected animals. Sequences were sampled longitudinally from several lymphoid and non-lymphoid tissues, including individual lobes within the brain at necropsy, for four macaques; two animals were sacrificed at 21 days post-infection (p.i.) to evaluate early viral seeding of the brain. Bayesian phylodynamic and phylogeographic analyses of the sequence data were used to ascertain viral population dynamics and gene flow between peripheral and brain tissues, respectively. A steady increase in viral effective population size, with a peak occurring at ~50-80 days p.i., was observed across all longitudinally monitored macaques. Phylogeographic analysis indicated continual viral seeding of the brain from several peripheral tissues throughout infection, with the last migration event before terminal illness occurring in all macaques from cells within the bone marrow. The results strongly supported the role of infected bone marrow cells in HIV/SIV neuropathogenesis. In addition, our work demonstrated the applicability of Bayesian phylogeography to intra-host studies in order to assess the interplay between viral evolution and pathogenesis.
authors.affiliation: Emerging Pathogens Institute, University of Florida, Gainesville, FL, USA.|Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Strickland
authors.affiliation: Emerging Pathogens Institute, University of Florida, Gainesville, FL, USA.|Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Brittany D
authors.initials: BD
authors.lastname: Rife
authors.affiliation: Bioinfoexperts LLC, Thibodaux, LA, USA.
authors.forename: Susanna L
authors.initials: SL
authors.lastname: Lamers
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Nolan
authors.affiliation: Emerging Pathogens Institute, University of Florida, Gainesville, FL, USA.|Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Nazle M C
authors.initials: NMC
authors.lastname: Veras
authors.affiliation: Emerging Pathogens Institute, University of Florida, Gainesville, FL, USA.|Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Mattia C F
authors.initials: MCF
authors.lastname: Prosperi
authors.affiliation: Department of Biology, Boston College, Chestnut Hill, MA, USA.
authors.forename: Tricia H
authors.initials: TH
authors.lastname: Burdo
authors.affiliation: Department of Biology, Boston College, Chestnut Hill, MA, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Autissier
authors.affiliation: Department of Biology, Boston College, Chestnut Hill, MA, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Nowlin
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Maureen M
authors.initials: MM
authors.lastname: Goodenow
authors.affiliation: Departments of Biomathematics, Biostatistics and Human Genetics, University of California (UCLA), Los Angeles, CA, USA.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Suchard
authors.affiliation: Department of Biology, Boston College, Chestnut Hill, MA, USA.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Williams
authors.affiliation: Emerging Pathogens Institute, University of Florida, Gainesville, FL, USA.|Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Salemi
mesh_terms: D000818:Animals; D001921:Brain / Q000821:virology; D018414:CD8-Positive T-Lymphocytes; D002452:Cell Count; D018792:Encephalitis, Viral / Q000821:virology*; D007694:Killer Cells, Natural; D008253:Macaca mulatta; D016097:Simian Acquired Immunodeficiency Syndrome / Q000473:pathology / Q000821:virology*; D015302:Simian Immunodeficiency Virus; D013997:Time Factors