5 years ago

Insights into the impact of CD8+ immune modulation on HIV evolutionary dynamics in distinct anatomical compartments using SIV-infected macaque models of AIDS progression.

A thorough understanding of the role of HIV intra-host evolution in AIDS pathogenesis has been limited by the need for longitudinally sampled viral sequences from the vast target space within the host, which are often difficult to obtain from human subjects. CD8+ lymphocyte-depleted macaques infected with simian immunodeficiency virus (SIV) provide an increasingly utilized model of pathogenesis due to similar clinical manifestations as HIV-1 infection and AIDS progression, as well as characteristic rapid disease onset. Comparison of this model with SIV-infected non-CD8+ lymphocyte-depleted macaques also provides a unique opportunity to investigate the role of CD8+ cells in viral evolution and population dynamics throughout the duration of infection. Using several different phylogenetic methods, we analyzed viral gp120 sequences obtained from extensive longitudinal sampling of multiple tissues and enriched leukocyte populations from SIVmac251-infected macaques, with or without CD8+ lymphocyte depletion. SIV evolutionary and selection patterns in non-CD8+ lymphocyte-depleted animals were characterized by sequential population turnover and continual viral adaptation, a scenario readily comparable to intra-host evolutionary patterns during human HIV infection in the absence of antiretroviral therapy. Alternatively, animals that were CD8+ lymphocyte depleted exhibited greater variation in population dynamics among tissues and cell populations over the course of infection. Our findings highlight the major role for CD8+ lymphocytes in prolonging disease progression through continual control of SIV sub-populations from varying anatomical compartments and the potential for greater independent viral evolutionary behavior among these compartments in response to immune modulation.IMPORTANCE Although developments in combined antiretroviral therapy (cART) strategies have successfully prolonged AIDS onset in HIV-1-infected individuals, a functional cure has yet to be found. Improvement of drug interventions for a virus that is able to infect a wide range of tissues and cell types requires a thorough understanding of viral adaptation and infection dynamics within this target milieu. Although difficult to accomplish in the human host, longitudinal sampling of multiple anatomical locations is readily accessible in the SIV-infected macaque models of neuroAIDS. The significance of our research is in identifying the impact of immune modulation, through differing immune selective pressure, on viral evolutionary behavior in a multitude of anatomical compartments. The results provide evidence encouraging the development of a more sophisticated model that considers a network of individual viral subpopulations within the host with differing infection and transmission dynamics, which is necessary for more effective treatment strategies.

Publisher URL: http://doi.org/10.1128/JVI.01162-17

DOI: 10.1128/JVI.01162-17

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