Spatiotemporal dynamics of simian immunodeficiency virus brain infection in CD8+ lymphocyte-depleted rhesus macaques with neuroAIDS

Samantha L Strickland, Brittany D Rife, Susanna L Lamers, David J Nolan, Nazle M C Veras, Mattia C F Prosperi, Tricia H Burdo, Patrick Autissier, Brian Nowlin, Maureen M Goodenow, Marc A Suchard, Kenneth C Williams, Marco Salemi

Despite the success of combined antiretroviral therapy in controlling viral replication in HIV-infected individuals, HIV-associated neurocognitive disorders (Manganaro et al., 2014), commonly referred to as neuroAIDS, remain a frequent and poorly understood complication. Infection of CD8+ lymphocyte-depleted rhesus macaques with SIVmac251 viral swarm is a well-established rapid disease model of neuroAIDS that has provided critical insight into HAND onset and progression. However, no studies so far have characterized in depth the relationship between intra-host viral evolution and pathogenesis in this model. 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 (dpi) 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 approximately 50-80 dpi, 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 support the role of infected bone marrow cells in HIV/SIV neuropathogenesis. In addition, our work demonstrates the applicability of Bayesian phylogeography to intra-host studies in order to assess the interplay between viral evolution and pathogenesis.