Importance of the N-Distal AP-2 Binding Element in Nef for Simian Immunodeficiency Virus Replication and Pathogenicity in Rhesus Macaques
| Autor: | Jonathan L. Heeney, Nicole Stolte, Kerstin Mätz-Rensing, Jacek Skowronski, Matthias Brenner, Christiane Stahl-Hennig, Jan Münch, Monika Franz, Michael Schindler, Frank Kirchhoff, Katarzyna Hrecka, Steffen Wildum, Dietmar Fuchs, Peter ten Haaft, Tomek Swigut |
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| Rok vydání: | 2006 |
| Předmět: |
Time Factors
viruses Molecular Sequence Data Immunology Adaptor Protein Complex 2 Biology Virus Replication medicine.disease_cause Microbiology Gene Products nef Virus Cell Line Virology medicine Animals Humans Amino Acid Sequence Alleles Infectivity Mutation Binding Sites Point mutation DNA replication Genetic Variation virus diseases Simian immunodeficiency virus Macaca mulatta Viral replication Insect Science Acute Disease Lentivirus Infections Pathogenesis and Immunity Simian Immunodeficiency Virus Sequence Alignment Viral load Protein Binding |
| Zdroj: | Journal of Virology. 80:4469-4481 |
| ISSN: | 1098-5514 0022-538X |
| Popis: | Point mutations in SIVmac239 Nef disrupting CD4 downmodulation and enhancement of virion infectivity attenuate viral replication in acutely infected rhesus macaques, but changes selected later in infection fully restore Nef function (A. J. Iafrate et al., J. Virol. 74:9836-9844, 2000). To further evaluate the relevance of these Nef functions for viral persistence and disease progression, we analyzed an SIVmac239 Nef mutant containing a deletion of amino acids Q64 to N67 (Δ64-67Nef). This mutation inactivates the N-distal AP-2 clathrin adaptor binding element and disrupts the abilities of Nef to downregulate CD4, CD28 and CXCR4 and to stimulate viral replication in vitro. However, it does not impair the downmodulation of CD3 and class I major histocompatibility complex (MHC-I) or MHC-II and the upregulation of the MHC-II-associated invariant chain, and it has only a moderate effect on the enhancement of virion infectivity. Replication of the Δ64-67Nef variant in acutely infected macaques was intermediate between grosslynef-deleted and wild-type SIVmac239. Subsequently, three of six macaques developed moderate to high viral loads and developed disease, whereas the remaining animals efficiently controlled SIV replication and showed a more attenuated clinical course of infection. Sequence analysis revealed that the deletion innefwas not repaired in any of these animals. However, some changes that slightly enhanced the ability of Nef to downmodulate CD4 and moderately increased Nef-mediated enhancement of viral replication and infectivity in vitro were observed in macaques developing high viral loads. Our results imply that both the Nef functions that were disrupted by the Δ64-67 mutation and the activities that remained intact contribute to viral pathogenicity. |
| Databáze: | OpenAIRE |
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