Noninfectious retrovirus particles drive the APOBEC3/Rfv3 dependent neutralizing antibody response.
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...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2011-10-01
|
| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC3188525?pdf=render |
| _version_ | 1818529505675837440 |
|---|---|
| author | Diana S Smith Kejun Guo Bradley S Barrett Karl J Heilman Leonard H Evans Kim J Hasenkrug Warner C Greene Mario L Santiago |
| author_facet | Diana S Smith Kejun Guo Bradley S Barrett Karl J Heilman Leonard H Evans Kim J Hasenkrug Warner C Greene Mario L Santiago |
| author_sort | Diana S Smith |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T17:07:44Z |
| format | Article |
| id | doaj.art-c55e999576e74449a8b3de8fc049b487 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-11T17:07:44Z |
| publishDate | 2011-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-c55e999576e74449a8b3de8fc049b4872022-12-22T00:57:38ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742011-10-01710e100228410.1371/journal.ppat.1002284Noninfectious retrovirus particles drive the APOBEC3/Rfv3 dependent neutralizing antibody response.Diana S SmithKejun GuoBradley S BarrettKarl J HeilmanLeonard H EvansKim J HasenkrugWarner C GreeneMario L SantiagoMembers 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.http://europepmc.org/articles/PMC3188525?pdf=render |
| spellingShingle | Diana S Smith Kejun Guo Bradley S Barrett Karl J Heilman Leonard H Evans Kim J Hasenkrug Warner C Greene Mario L Santiago Noninfectious retrovirus particles drive the APOBEC3/Rfv3 dependent neutralizing antibody response. PLoS Pathogens |
| title | Noninfectious retrovirus particles drive the APOBEC3/Rfv3 dependent neutralizing antibody response. |
| title_full | Noninfectious retrovirus particles drive the APOBEC3/Rfv3 dependent neutralizing antibody response. |
| title_fullStr | Noninfectious retrovirus particles drive the APOBEC3/Rfv3 dependent neutralizing antibody response. |
| title_full_unstemmed | Noninfectious retrovirus particles drive the APOBEC3/Rfv3 dependent neutralizing antibody response. |
| title_short | Noninfectious retrovirus particles drive the APOBEC3/Rfv3 dependent neutralizing antibody response. |
| title_sort | noninfectious retrovirus particles drive the apobec3 rfv3 dependent neutralizing antibody response |
| url | http://europepmc.org/articles/PMC3188525?pdf=render |
| work_keys_str_mv | AT dianassmith noninfectiousretrovirusparticlesdrivetheapobec3rfv3dependentneutralizingantibodyresponse AT kejunguo noninfectiousretrovirusparticlesdrivetheapobec3rfv3dependentneutralizingantibodyresponse AT bradleysbarrett noninfectiousretrovirusparticlesdrivetheapobec3rfv3dependentneutralizingantibodyresponse AT karljheilman noninfectiousretrovirusparticlesdrivetheapobec3rfv3dependentneutralizingantibodyresponse AT leonardhevans noninfectiousretrovirusparticlesdrivetheapobec3rfv3dependentneutralizingantibodyresponse AT kimjhasenkrug noninfectiousretrovirusparticlesdrivetheapobec3rfv3dependentneutralizingantibodyresponse AT warnercgreene noninfectiousretrovirusparticlesdrivetheapobec3rfv3dependentneutralizingantibodyresponse AT mariolsantiago noninfectiousretrovirusparticlesdrivetheapobec3rfv3dependentneutralizingantibodyresponse |