title: Host factors determine differential disease progression after infection with nef-deleted simian immunodeficiency virus.
abstract: Infection of macaques with live attenuated simian immunodeficiency virus (SIV) usually results in long-lasting efficient protection against infection with pathogenic immunodeficiency viruses. However, attenuation by deletion of regulatory genes such as nef is not complete, leading to a high viral load and fatal disease in some animals. To characterize immunological parameters and polymorphic host factors, we studied 17 rhesus macaques infected with attenuated SIVmac239ΔNU. Eight animals were able to control viral replication, whereas the remaining animals (non-controllers) displayed variable set-point viral loads. Peak viral load at 2 weeks post-infection (p.i.) correlated significantly with set-point viral load (P<0.0001). CD4(+) T-cell frequencies differed significantly soon after infection between controllers and non-controllers. Abnormal B-cell activation previously ascribed to Nef function could already be observed in non-controllers 8 weeks after infection despite the absence of Nef. Two non-controllers developed an AIDS-like disease within 102 weeks p.i. Virus from these animals transmitted to naïve animals replicated at low levels and the recipients did not develop immunodeficiency. This suggested that host factors determined differential viral load and subsequent disease course. Known Mhc class I alleles associated with disease progression in SIV WT infection only marginally influenced the viral load in Δnef-infected animals. Protection from SIVmac251 was associated with homozygosity for MHC class II in conjunction with a TLR7 polymorphism and showed a trend with initial viral replication. We speculated that host factors whose effects were usually masked by Nef were responsible for the different disease courses in individual animals upon infection with nef-deleted viruses.
authors.affiliation: Tumor Immunology Lab, Hematology and Oncology, Medical University Innsbruck and Tyrolean Cancer Research Institute, Innsbruck, Austria.
authors.forename: Sieghart
authors.initials: S
authors.lastname: Sopper
authors.affiliation: Pathology Unit, German Primate Center, Leibniz Institute for Primate Research, Goettingen, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Mätz-Rensing
authors.affiliation: Unit of Infection Models, German Primate Center, Leibniz Institute for Primate Research, Kellnerweg 4, 37077 Goettingen, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Mühl
authors.affiliation: Department of Veterinary Medicine, The University of Cambridge, Cambridge, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Heeney
authors.affiliation: Unit of Infection Models, German Primate Center, Leibniz Institute for Primate Research, Kellnerweg 4, 37077 Goettingen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Stahl-Hennig
authors.affiliation: Unit of Infection Models, German Primate Center, Leibniz Institute for Primate Research, Kellnerweg 4, 37077 Goettingen, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Sauermann
mesh_terms: D000818:Animals; D018450:Disease Progression; D015693:Gene Products, nef / Q000172:deficiency*; D054884:Host-Pathogen Interactions; D008253:Macaca mulatta; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D019562:Viral Load
chemical_list: D015693:Gene Products, nef