title: Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations.
abstract: Despite antiretroviral therapy (ART), human immunodeficiency virus (HIV)-1 persists in a stable latent reservoir, primarily in resting memory CD4(+) T cells. This reservoir presents a major barrier to the cure of HIV-1 infection. To purge the reservoir, pharmacological reactivation of latent HIV-1 has been proposed and tested both in vitro and in vivo. A key remaining question is whether virus-specific immune mechanisms, including cytotoxic T lymphocytes (CTLs), can clear infected cells in ART-treated patients after latency is reversed. Here we show that there is a striking all or none pattern for CTL escape mutations in HIV-1 Gag epitopes. Unless ART is started early, the vast majority (>98%) of latent viruses carry CTL escape mutations that render infected cells insensitive to CTLs directed at common epitopes. To solve this problem, we identified CTLs that could recognize epitopes from latent HIV-1 that were unmutated in every chronically infected patient tested. Upon stimulation, these CTLs eliminated target cells infected with autologous virus derived from the latent reservoir, both in vitro and in patient-derived humanized mice. The predominance of CTL-resistant viruses in the latent reservoir poses a major challenge to viral eradication. Our results demonstrate that chronically infected patients retain a broad-spectrum viral-specific CTL response and that appropriate boosting of this response may be required for the elimination of the latent reservoir.
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Deng
authors.affiliation: 1] Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Pertea
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Rongvaux
authors.affiliation: Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut 06510, USA.
authors.forename: Leyao
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Durand
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Ghiaur
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Lai
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Holly L
authors.initials: HL
authors.lastname: McHugh
authors.affiliation: Deep Sequencing and Microarray Core, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Haiping
authors.initials: H
authors.lastname: Hao
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Margolick
authors.affiliation: Regeneron Pharmaceuticals Inc., Tarrytown, New York 10591, USA.
authors.forename: Cagan
authors.initials: C
authors.lastname: Gurer
authors.affiliation: Regeneron Pharmaceuticals Inc., Tarrytown, New York 10591, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.affiliation: Regeneron Pharmaceuticals Inc., Tarrytown, New York 10591, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Valenzuela
authors.affiliation: Regeneron Pharmaceuticals Inc., Tarrytown, New York 10591, USA.
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California 94110, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Till
authors.initials: T
authors.lastname: Strowig
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Priti
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Janet D
authors.initials: JD
authors.lastname: Siliciano
authors.affiliation: 1] Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Salzberg
authors.affiliation: 1] Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA [2] Howard Hughes Medical Institute, New Haven, Connecticut 06510, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Shan
authors.affiliation: 1] Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Howard Hughes Medical Institute, Baltimore, Maryland 21205, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Siliciano
mesh_terms: D000208:Acute Disease / Q000628:therapy; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000821:virology; D002908:Chronic Disease / Q000188:drug therapy; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D005260:Female; D005799:Genes, Dominant / Q000235:genetics*; D005814:Genes, Viral / Q000235:genetics*; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development / Q000276:immunology*; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D012367:RNA, Viral / Q000097:blood; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019562:Viral Load / Q000187:drug effects; D017735:Virus Latency / Q000235:genetics / Q000276:immunology*; D014779:Virus Replication / Q000276:immunology; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology
chemical_list: D019380:Anti-HIV Agents; D018984:Epitopes, T-Lymphocyte; D012367:RNA, Viral; D054301:gag Gene Products, Human Immunodeficiency Virus