HLA-B57/B5801 Human Immunodeficiency Virus Type 1 Elite Controllers Select for Rare Gag Variants Associated with Reduced Viral Replication Capacity and Strong Cytotoxic T-Lymphotye Recognition

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Published inJournal of Virology Vol. 83; no. 6; pp. 2743 - 2755
Main Authors Miura, Toshiyuki, Brockman, Mark A., Schneidewind, Arne, Lobritz, Michael, Pereyra, Florencia, Rathod, Almas, Block, Brian L., Brumme, Zabrina L., Brumme, Chanson J., Baker, Brett, Rothchild, Alissa C., Li, Bin, Trocha, Alicja, Cutrell, Emily, Frahm, Nicole, Brander, Christian, Toth, Ildiko, Arts, Eric J., Allen, Todd M., Walker, Bruce D.
Format Journal Article
LanguageEnglish
Published American Society for Microbiology 15.03.2009
American Society for Microbiology (ASM)
Subjects
Human immunodeficiency virus 1
Pathogenesis and Immunity
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Abstract Erratum ( vol. 83 , p. 5961 ) Article Usage Stats Services JVI Citing Articles Google Scholar PubMed Related Content Social Bookmarking CiteULike Delicious Digg Facebook Google+ Mendeley Reddit StumbleUpon Twitter current issue Spotlights in the Current Issue JVI About JVI Subscribers Authors Reviewers Advertisers Inquiries from the Press Permissions & Commercial Reprints ASM Journals Public Access Policy JVI RSS Feeds 1752 N Street N.W. • Washington DC 20036 202.737.3600 • 202.942.9355 fax • journals@asmusa.org Print ISSN: 0022-538X Online ISSN: 1098-5514 Copyright © 2014 by the American Society for Microbiology.   For an alternate route to JVI .asm.org, visit: JVI       
AbstractList Erratum ( vol. 83 , p. 5961 ) Article Usage Stats Services JVI Citing Articles Google Scholar PubMed Related Content Social Bookmarking CiteULike Delicious Digg Facebook Google+ Mendeley Reddit StumbleUpon Twitter current issue Spotlights in the Current Issue JVI About JVI Subscribers Authors Reviewers Advertisers Inquiries from the Press Permissions & Commercial Reprints ASM Journals Public Access Policy JVI RSS Feeds 1752 N Street N.W. • Washington DC 20036 202.737.3600 • 202.942.9355 fax • journals@asmusa.org Print ISSN: 0022-538X Online ISSN: 1098-5514 Copyright © 2014 by the American Society for Microbiology.   For an alternate route to JVI .asm.org, visit: JVI       
Human immunodeficiency virus type 1 (HIV-1) elite controllers (EC) maintain viremia below the limit of commercial assay detection (<50 RNA copies/ml) in the absence of antiviral therapy, but the mechanisms of control remain unclear. HLA-B57 and the closely related allele B*5801 are particularly associated with enhanced control and recognize the same Gag 240-249 TW10 epitope. The typical escape mutation (T242N) within this epitope diminishes viral replication capacity in chronically infected persons; however, little is known about TW10 epitope sequences in residual replicating viruses in B57/B*5801 EC and the extent to which mutations within this epitope may influence steady-state viremia. Here we analyzed TW10 in a total of 50 B57/B*5801-positive subjects (23 EC and 27 viremic subjects). Autologous plasma viral sequences from both EC and viremic subjects frequently harbored the typical cytotoxic T-lymphocyte (CTL)-selected mutation T242N (15/23 sequences [65.2%] versus 23/27 sequences [85.1%], respectively; P = 0.18). However, other unique mutants were identified in HIV controllers, both within and flanking TW10, that were associated with an even greater reduction in viral replication capacity in vitro. In addition, strong CTL responses to many of these unique TW10 variants were detected by gamma interferon-specific enzyme-linked immunospot assay. These data suggest a dual mechanism for durable control of HIV replication, consisting of viral fitness loss resulting from CTL escape mutations together with strong CD8 T-cell immune responses to the arising variant epitopes.
Human immunodeficiency virus type 1 (HIV-1) elite controllers (EC) maintain viremia below the limit of commercial assay detection (<50 RNA copies/ml) in the absence of antiviral therapy, but the mechanisms of control remain unclear. HLA-B57 and the closely related allele B*5801 are particularly associated with enhanced control and recognize the same Gag240-249 TW10 epitope. The typical escape mutation (T242N) within this epitope diminishes viral replication capacity in chronically infected persons; however, little is known about TW10 epitope sequences in residual replicating viruses in B57/B*5801 EC and the extent to which mutations within this epitope may influence steady-state viremia. Here we analyzed TW10 in a total of 50 B57/B*5801-positive subjects (23 EC and 27 viremic subjects). Autologous plasma viral sequences from both EC and viremic subjects frequently harbored the typical cytotoxic T-lymphocyte (CTL)-selected mutation T242N (15/23 sequences [65.2%] versus 23/27 sequences [85.1%], respectively; P = 0.18). However, other unique mutants were identified in HIV controllers, both within and flanking TW10, that were associated with an even greater reduction in viral replication capacity in vitro. In addition, strong CTL responses to many of these unique TW10 variants were detected by gamma interferon-specific enzyme-linked immunospot assay. These data suggest a dual mechanism for durable control of HIV replication, consisting of viral fitness loss resulting from CTL escape mutations together with strong CD8 T-cell immune responses to the arising variant epitopes.
Author Chanson J. Brumme
Todd M. Allen
Alicja Trocha
Nicole Frahm
Brian L. Block
Mark A. Brockman
Toshiyuki Miura
Arne Schneidewind
Alissa C. Rothchild
Bruce D. Walker
Bin Li
Zabrina L. Brumme
Eric J. Arts
Michael Lobritz
Christian Brander
Almas Rathod
Emily Cutrell
Florencia Pereyra
Ildiko Toth
Brett Baker
AuthorAffiliation Ragon Institute (formerly Partners AIDS Research Center), Massachusetts General Hospital, Charlestown, Massachusetts 02129, 1 Howard Hughes Medical Institute, Chevy Chase, Maryland, 2 Harvard Medical School, Boston, Massachusetts, 3 Case Western Reserve University, Cleveland, Ohio 4
AuthorAffiliation_xml – name: Ragon Institute (formerly Partners AIDS Research Center), Massachusetts General Hospital, Charlestown, Massachusetts 02129, 1 Howard Hughes Medical Institute, Chevy Chase, Maryland, 2 Harvard Medical School, Boston, Massachusetts, 3 Case Western Reserve University, Cleveland, Ohio 4
Author_xml – sequence: 1
  givenname: Toshiyuki
  surname: Miura
  fullname: Miura, Toshiyuki
  organization: Ragon Institute (formerly Partners AIDS Research Center), Massachusetts General Hospital, Charlestown, Massachusetts 02129, Howard Hughes Medical Institute, Chevy Chase, Maryland, Harvard Medical School, Boston, Massachusetts
– sequence: 2
  givenname: Mark A.
  surname: Brockman
  fullname: Brockman, Mark A.
  organization: Ragon Institute (formerly Partners AIDS Research Center), Massachusetts General Hospital, Charlestown, Massachusetts 02129, Harvard Medical School, Boston, Massachusetts
– sequence: 3
  givenname: Arne
  surname: Schneidewind
  fullname: Schneidewind, Arne
  organization: Ragon Institute (formerly Partners AIDS Research Center), Massachusetts General Hospital, Charlestown, Massachusetts 02129, Harvard Medical School, Boston, Massachusetts
– sequence: 4
  givenname: Michael
  surname: Lobritz
  fullname: Lobritz, Michael
  organization: Case Western Reserve University, Cleveland, Ohio
– sequence: 5
  givenname: Florencia
  surname: Pereyra
  fullname: Pereyra, Florencia
  organization: Ragon Institute (formerly Partners AIDS Research Center), Massachusetts General Hospital, Charlestown, Massachusetts 02129, Harvard Medical School, Boston, Massachusetts
– sequence: 6
  givenname: Almas
  surname: Rathod
  fullname: Rathod, Almas
  organization: Ragon Institute (formerly Partners AIDS Research Center), Massachusetts General Hospital, Charlestown, Massachusetts 02129
– sequence: 7
  givenname: Brian L.
  surname: Block
  fullname: Block, Brian L.
  organization: Ragon Institute (formerly Partners AIDS Research Center), Massachusetts General Hospital, Charlestown, Massachusetts 02129
– sequence: 8
  givenname: Zabrina L.
  surname: Brumme
  fullname: Brumme, Zabrina L.
  organization: Ragon Institute (formerly Partners AIDS Research Center), Massachusetts General Hospital, Charlestown, Massachusetts 02129, Harvard Medical School, Boston, Massachusetts
– sequence: 9
  givenname: Chanson J.
  surname: Brumme
  fullname: Brumme, Chanson J.
  organization: Ragon Institute (formerly Partners AIDS Research Center), Massachusetts General Hospital, Charlestown, Massachusetts 02129
– sequence: 10
  givenname: Brett
  surname: Baker
  fullname: Baker, Brett
  organization: Ragon Institute (formerly Partners AIDS Research Center), Massachusetts General Hospital, Charlestown, Massachusetts 02129
– sequence: 11
  givenname: Alissa C.
  surname: Rothchild
  fullname: Rothchild, Alissa C.
  organization: Ragon Institute (formerly Partners AIDS Research Center), Massachusetts General Hospital, Charlestown, Massachusetts 02129
– sequence: 12
  givenname: Bin
  surname: Li
  fullname: Li, Bin
  organization: Ragon Institute (formerly Partners AIDS Research Center), Massachusetts General Hospital, Charlestown, Massachusetts 02129, Harvard Medical School, Boston, Massachusetts
– sequence: 13
  givenname: Alicja
  surname: Trocha
  fullname: Trocha, Alicja
  organization: Ragon Institute (formerly Partners AIDS Research Center), Massachusetts General Hospital, Charlestown, Massachusetts 02129, Howard Hughes Medical Institute, Chevy Chase, Maryland
– sequence: 14
  givenname: Emily
  surname: Cutrell
  fullname: Cutrell, Emily
  organization: Ragon Institute (formerly Partners AIDS Research Center), Massachusetts General Hospital, Charlestown, Massachusetts 02129
– sequence: 15
  givenname: Nicole
  surname: Frahm
  fullname: Frahm, Nicole
  organization: Ragon Institute (formerly Partners AIDS Research Center), Massachusetts General Hospital, Charlestown, Massachusetts 02129, Harvard Medical School, Boston, Massachusetts
– sequence: 16
  givenname: Christian
  surname: Brander
  fullname: Brander, Christian
  organization: Ragon Institute (formerly Partners AIDS Research Center), Massachusetts General Hospital, Charlestown, Massachusetts 02129, Harvard Medical School, Boston, Massachusetts
– sequence: 17
  givenname: Ildiko
  surname: Toth
  fullname: Toth, Ildiko
  organization: Ragon Institute (formerly Partners AIDS Research Center), Massachusetts General Hospital, Charlestown, Massachusetts 02129
– sequence: 18
  givenname: Eric J.
  surname: Arts
  fullname: Arts, Eric J.
  organization: Case Western Reserve University, Cleveland, Ohio
– sequence: 19
  givenname: Todd M.
  surname: Allen
  fullname: Allen, Todd M.
  organization: Ragon Institute (formerly Partners AIDS Research Center), Massachusetts General Hospital, Charlestown, Massachusetts 02129, Harvard Medical School, Boston, Massachusetts
– sequence: 20
  givenname: Bruce D.
  surname: Walker
  fullname: Walker, Bruce D.
  organization: Ragon Institute (formerly Partners AIDS Research Center), Massachusetts General Hospital, Charlestown, Massachusetts 02129, Howard Hughes Medical Institute, Chevy Chase, Maryland, Harvard Medical School, Boston, Massachusetts
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Corresponding author. Mailing address: Ragon Institute, Massachusetts General Hospital, 149 13th St., Room 5212, Charlestown, MA 02129. Phone for Bruce D. Walker: (617) 724-8332. Fax: (617) 726-4691. E-mail: bwalker@partners.org. Phone for Toshiyuki Miura: (617) 643-2836. Fax: (617) 726-5411. E-mail: miura523@hotmail.com
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Snippet Erratum ( vol. 83 , p. 5961 ) Article Usage Stats Services JVI Citing Articles Google Scholar PubMed Related Content Social Bookmarking CiteULike Delicious...
Human immunodeficiency virus type 1 (HIV-1) elite controllers (EC) maintain viremia below the limit of commercial assay detection (<50 RNA copies/ml) in the...
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SubjectTerms Human immunodeficiency virus 1
Pathogenesis and Immunity
Title HLA-B57/B5801 Human Immunodeficiency Virus Type 1 Elite Controllers Select for Rare Gag Variants Associated with Reduced Viral Replication Capacity and Strong Cytotoxic T-Lymphotye Recognition
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