biologically-directed modeling reflects cytolytic clearance of siv-infected cells in vivo in macaquesbiologically-directed建模反映siv-infected细胞的溶细胞的间隙在猕猴体内.pdfVIP

Biologically-Directed Modeling Reflects Cytolytic Clearance of SIV-Infected Cells In Vivo in Macaques 1 2 W. David Wick *, Otto O. Yang 1Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America, 2 Geffen School of Medicine, Department of Medicine/Department of Microbiology, Immunology, and Molecular Genetics/UCLA AIDS Institute, University of California Los Angeles, Los Angeles, California, United States of America Abstract The disappointing outcomes of cellular immune-based vaccines against HIV-1 despite strong evidence for the protective role of CD8+ T lymphocytes (CTLs) has prompted revisiting the mechanisms of cellular immunity. Prior data from experiments examining the kinetics of Simian Immunodeficiency Virus (SIV) clearance in infected macaques with or without in vivo CD8 depletion were interpreted as refuting the concept that CTLs suppress SIV/HIV by direct killing of infected cells. Here we briefly review the biological evidence for CTL cytolytic activity in viral infections, and utilize biologically-directed modeling to assess the possibility of a killing mechanism for the antiviral effect of CTLs, taking into account the generation, proliferation, and survival of activated CD4+ and CD8+ T lymphocytes, as well as the life cycle of the virus. Our analyses of the published macaque data using these models support a killing mechanism, when one considers T lymphocyte and HIV-1 lifecycles, and factors such as the eclipse period before release of virions by infected cells, an exponential pattern of virion production by infected cells, and a variable lifespan for acutely infected cells. We conclude that for SIV/HIV pathogenesis, CTLs deserve their reputation as being cytolytic. Citation: Wi