title: HIV control is mediated in part by CD8+ T-cell targeting of specific epitopes.
abstract: We investigated the hypothesis that the correlation between the class I HLA types of an individual and whether that individual spontaneously controls HIV-1 is mediated by the targeting of specific epitopes by CD8(+) T cells. By measuring gamma interferon enzyme-linked immunosorbent spot (ELISPOT) assay responses to a panel of 257 optimally defined epitopes in 341 untreated HIV-infected persons, including persons who spontaneously control viremia, we found that the correlation between HLA types and control is mediated by the targeting of specific epitopes. Moreover, we performed a graphical model-based analysis that suggested that the targeting of specific epitopes is a cause of such control--that is, some epitopes are protective rather than merely associated with control--and identified eight epitopes that are significantly protective. In addition, we use an in silico analysis to identify protein regions where mutations are likely to affect the stability of a protein, and we found that the protective epitopes identified by the ELISPOT analysis correspond almost perfectly to such regions. This in silico analysis thus suggests a possible mechanism for control and could be used to identify protective epitopes that are not often targeted in natural infection but that may be potentially useful in a vaccine. Our analyses thus argue for the inclusion (and exclusion) of specific epitopes in an HIV vaccine.
  
  
  OBJECTIVE
  Some individuals naturally control HIV replication in the absence of antiretroviral therapy, and this ability to control is strongly correlated with the HLA class I alleles that they express. Here, in a large-scale experimental study, we provide evidence that this correlation is mediated largely by the targeting of specific CD8(+) T-cell epitopes, and we identify eight epitopes that are likely to cause control. In addition, we provide an in silico analysis indicating that control occurs because mutations within these epitopes change the stability of the protein structures. This in silico analysis also identified additional epitopes that are not typically targeted in natural infection but may lead to control when included in a vaccine, provided that other epitopes that would otherwise distract the immune system from targeting them are excluded from the vaccine.
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Florencia
authors.initials: F
authors.lastname: Pereyra
authors.affiliation: Microsoft Research, Los Angeles, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
authors.affiliation: Microsoft Research, Los Angeles, California, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Carlson
authors.affiliation: Microsoft Research, Redmond, Washington, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Kadie
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.
authors.forename: Damien Z
authors.initials: DZ
authors.lastname: Soghoian
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Karel
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.
authors.forename: Ariel
authors.initials: A
authors.lastname: Goldenthal
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.
authors.forename: Oliver B
authors.initials: OB
authors.lastname: Davis
authors.affiliation: Microsoft Research, Los Angeles, California, USA.
authors.forename: Charles E
authors.initials: CE
authors.lastname: DeZiel
authors.affiliation: Microsoft Research, Los Angeles, California, USA.
authors.forename: Tienho
authors.initials: T
authors.lastname: Lin
authors.affiliation: Microsoft Research, Los Angeles, California, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Peng
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA.
authors.forename: Alicja
authors.initials: A
authors.lastname: Piechocka
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Boston, Massachusetts, USA Howard Hughes Medical Institute, Chevy Chase, Maryland, USA bwalker@partners.org.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
mesh_terms: D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015331:Cohort Studies; D019295:Computational Biology; D058501:Enzyme-Linked Immunospot Assay; D000939:Epitopes / Q000276:immunology*; D005260:Female; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D008297:Male; D008875:Middle Aged
chemical_list: D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D007371:Interferon-gamma