Noninfectious Retrovirus Particles Drive the Apobec3/Rfv3 Dependent Neutralizing Antibody Response

PLoS Pathogens

Diana S. Smith¹  Kejun Guo¹  Karl J. Heilman¹  Bradley S. Barrett¹  Mario L. Santiago²  Warner C. Greene³  Kim J. Hasenkrug⁴  Leonard H. Evans⁴ 

[1] Department of Medicine, University of Colorado Denver, Aurora, Colorado, United States of America;Departments of Medicine, Microbiology and Immunology, University of California San Francisco, San Francisco, California, United States of America;Gladstone Institute of Virology and Immunology, University of California San Francisco, San Francisco, California, United States of America;Rocky Mountain Laboratories, National Institutes of Allergy and Infectious Diseases, Hamilton, Montana, United States of America

关键词: Virions;    HIV-1;    B cells;    Viremia;    Antibody response;    Polymerase chain reaction;    Reverse transcription;    Antibodies;   

DOI  :  10.1371/journal.ppat.1002284

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Members of the APOBEC3 family of deoxycytidine deaminases counteract a broad range of retroviruses in vitro through an indirect mechanism that requires virion incorporation and inhibition of reverse transcription and/or hypermutation of minus strand transcripts in the next target cell. The selective advantage to the host of this indirect restriction mechanism remains unclear, but valuable insights may be gained by studying APOBEC3 function in vivo. Apobec3 was previously shown to encode Rfv3, a classical resistance gene that controls the recovery of mice from pathogenic Friend retrovirus (FV) infection by promoting a more potent neutralizing antibody (NAb) response. The underlying mechanism does not involve a direct effect of Apobec3 on B cell function. Here we show that while Apobec3 decreased titers of infectious virus during acute FV infection, plasma viral RNA loads were maintained, indicating substantial release of noninfectious particles in vivo. The lack of plasma virion infectivity was associated with a significant post-entry block during early reverse transcription rather than G-to-A hypermutation. The Apobec3-dependent NAb response correlated with IgG binding titers against native, but not detergent-lysed virions. These findings indicate that innate Apobec3 restriction promotes NAb responses by maintaining high concentrations of virions with native B cell epitopes, but in the context of low virion infectivity. Finally, Apobec3 restriction was found to be saturable in vivo, since increasing FV inoculum doses resulted in decreased Apobec3 inhibition. By analogy, maximizing the release of noninfectious particles by modulating APOBEC3 expression may improve humoral immunity against pathogenic human retroviral infections.

【 授权许可】

CC BY