Co-dependence of HTLV-1 p12 and p8 Functions in Virus Persistence

PLoS Pathogens

Maria Fernanda de Castro-Amarante¹  Martina Fiocchi¹  R. Cody Buchmann¹  Genoveffa Franchini¹  Claudio Fenizia¹  Robyn Washington Parks¹  Cynthia A. Pise-Masison¹  Dustin Edwards¹  David Venzon²  Izabela Bialuk³  Jean-Claude Walser⁴  Luiz Carlos Alcantara Jr⁵  Bernardo Galvão-Castro⁵  Antoine Gessain⁶  Katherine McKinnon⁷  Jhanelle Graham⁸  Steven Jacobson⁸  Yoshimi Enose-Akahata⁸ 

[1] Animal Models and Retroviral Vaccines Section, National Cancer Institute, Bethesda, Maryland, United States of America;Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland, United States of America;Department of General and Experimental Pathology, Medical University in Białystok, Białystok, Poland;Evolutionary Biology, Genetic Diversity Centre, University of Basel, Basel, Switzerland;Oswaldo Cruz Foundation Salvador, Bahia, Brazil;Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Département de Virologie, Batiment Lwoff, Institut Pasteur, Paris, France;Vaccine Branch Flow Cytometry Core Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America;Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, United States of America

关键词: HTLV-1;    T cells;    Macaque;    Polymerase chain reaction;    Monocytes;    Cloning;    Viral persistence;    latency;    Small interfering RNAs;   

DOI  :  10.1371/journal.ppat.1004454

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

HTLV-1 orf-I is linked to immune evasion, viral replication and persistence. Examining the orf-I sequence of 160 HTLV-1-infected individuals; we found polymorphism of orf-I that alters the relative amounts of p12 and its cleavage product p8. Three groups were identified on the basis of p12 and p8 expression: predominantly p12, predominantly p8 and balanced expression of p12 and p8. We found a significant association between balanced expression of p12 and p8 with high viral DNA loads, a correlate of disease development. To determine the individual roles of p12 and p8 in viral persistence, we constructed infectious molecular clones expressing p12 and p8 (D26), predominantly p12 (G29S) or predominantly p8 (N26). As we previously showed, cells expressing N26 had a higher level of virus transmission in vitro. However, when inoculated into Rhesus macaques, cells producing N26 virus caused only a partial seroconversion in 3 of 4 animals and only 1 of those animals was HTLV-1 DNA positive by PCR. None of the animals exposed to G29S virus seroconverted or had detectable viral DNA. In contrast, 3 of 4 animals exposed to D26 virus seroconverted and were HTLV-1 positive by PCR. In vitro studies in THP-1 cells suggested that expression of p8 was sufficient for productive infection of monocytes. Since orf-I plays a role in T-cell activation and recognition; we compared the CTL response elicited by CD4+ T-cells infected with the different HTLV-1 clones. Although supernatant p19 levels and viral DNA loads for all four infected lines were similar, a significant difference in Tax-specific HLA.A2-restricted killing was observed. Cells infected with Orf-I-knockout virus (12KO), G29S or N26 were killed by CTLs, whereas cells infected with D26 virus were resistant to CTL killing. These results indicate that efficient viral persistence and spread require the combined functions of p12 and p8.

【 授权许可】

CC BY