title: HERV-K-specific T cells eliminate diverse HIV-1/2 and SIV primary isolates.
abstract: The genetic diversity of HIV-1 represents a major challenge in vaccine development. In this study, we establish a rationale for eliminating HIV-1-infected cells by targeting cellular immune responses against stable human endogenous retroviral (HERV) antigens. HERV DNA sequences in the human genome represent the remnants of ancient infectious retroviruses. We show that the infection of CD4+ T cells with HIV-1 resulted in transcription of the HML-2 lineage of HERV type K [HERV-K(HML-2)] and the expression of Gag and Env proteins. HERV-K(HML-2)-specific CD8+ T cells obtained from HIV-1-infected human subjects responded to HIV-1-infected cells in a Vif-dependent manner in vitro. Consistent with the proposed mode of action, a HERV-K(HML-2)-specific CD8+ T cell clone exhibited comprehensive elimination of cells infected with a panel of globally diverse HIV-1, HIV-2, and SIV isolates in vitro. We identified a second T cell response that exhibited cross-reactivity between homologous HIV-1-Pol and HERV-K(HML-2)-Pol determinants, raising the possibility that homology between HIV-1 and HERVs plays a role in shaping, and perhaps enhancing, the T cell response to HIV-1. This justifies the consideration of HERV-K(HML-2)-specific and cross-reactive T cell responses in the natural control of HIV-1 infection and for exploring HERV-K(HML-2)-targeted HIV-1 vaccines and immunotherapeutics.
authors.affiliation: Department of Immunology, University of Toronto, and Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada. bjones.ut@gmail.com
authors.forename: R Brad
authors.initials: RB
authors.lastname: Jones
authors.forename: Keith E
authors.initials: KE
authors.lastname: Garrison
authors.forename: Shariq
authors.initials: S
authors.lastname: Mujib
authors.forename: Vesna
authors.initials: V
authors.lastname: Mihajlovic
authors.forename: Nasra
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authors.lastname: Aidarus
authors.forename: Diana V
authors.initials: DV
authors.lastname: Hunter
authors.forename: Eric
authors.initials: E
authors.lastname: Martin
authors.forename: Vivek M
authors.initials: VM
authors.lastname: John
authors.forename: Wei
authors.initials: W
authors.lastname: Zhan
authors.forename: Nabil F
authors.initials: NF
authors.lastname: Faruk
authors.forename: Gabor
authors.initials: G
authors.lastname: Gyenes
authors.forename: Neil C
authors.initials: NC
authors.lastname: Sheppard
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Priumboom-Brees
authors.forename: David A
authors.initials: DA
authors.lastname: Goodwin
authors.forename: Lianchun
authors.initials: L
authors.lastname: Chen
authors.forename: Melanie
authors.initials: M
authors.lastname: Rieger
authors.forename: Sophie
authors.initials: S
authors.lastname: Muscat-King
authors.forename: Peter T
authors.initials: PT
authors.lastname: Loudon
authors.forename: Cole
authors.initials: C
authors.lastname: Stanley
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Holditch
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Wong
authors.forename: Kiera
authors.initials: K
authors.lastname: Clayton
authors.forename: Erick
authors.initials: E
authors.lastname: Duan
authors.forename: Haihan
authors.initials: H
authors.lastname: Song
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Devi
authors.initials: D
authors.lastname: SenGupta
authors.forename: Ravi
authors.initials: R
authors.lastname: Tandon
authors.forename: Jonah B
authors.initials: JB
authors.lastname: Sacha
authors.forename: Mark A
authors.initials: MA
authors.lastname: Brockman
authors.forename: Erika
authors.initials: E
authors.lastname: Benko
authors.forename: Colin
authors.initials: C
authors.lastname: Kovacs
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Nixon
authors.forename: Mario A
authors.initials: MA
authors.lastname: Ostrowski
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D002478:Cells, Cultured; D020077:Endogenous Retroviruses / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D015967:Gene Expression Regulation, Viral; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000276:immunology / Q000302:isolation & purification / Q000502:physiology*; D015498:HIV-2 / Q000276:immunology / Q000302:isolation & purification / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D007111:Immunity, Cellular; D008969:Molecular Sequence Data; D015302:Simian Immunodeficiency Virus / Q000276:immunology / Q000302:isolation & purification / Q000502:physiology*; D015533:Transcriptional Activation; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016662:Virus Integration; D053586:Virus Internalization; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000502:physiology
chemical_list: D000956:Antigens, Viral; D015683:Gene Products, gag; D014759:Viral Envelope Proteins; D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1