HERV-K–specific T cells eliminate diverse HIV-1/2 and SIV primary isolates

• Published in: The Journal of clinical investigation Vol. 122; no. 12; pp. 4473 - 4489
• Main Authors: Jones, R. Brad, Garrison, Keith E., Mujib, Shariq, Mihajlovic, Vesna, Aidarus, Nasra, Hunter, Diana V., Martin, Eric, John, Vivek M., Zhan, Wei, Faruk, Nabil F., Gyenes, Gabor, Sheppard, Neil C., Priumboom-Brees, Ingrid M., Goodwin, David A., Chen, Lianchun, Rieger, Melanie, Muscat-King, Sophie, Loudon, Peter T., Stanley, Cole, Holditch, Sara J., Wong, Jessica C., Clayton, Kiera, Duan, Erick, Song, Haihan, Xu, Yang, SenGupta, Devi, Tandon, Ravi, Sacha, Jonah B., Brockman, Mark A., Benko, Erika, Kovacs, Colin, Nixon, Douglas F., Ostrowski, Mario A.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.12.2012
• Subjects: Amino Acid Sequence; Animals; Antigens; Antigens, Viral - genetics; Antigens, Viral - immunology; Antigens, Viral - metabolism; Biomedical research; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - virology; CD8 antigen; Cells; Cells, Cultured; Cross-reactivity; Endogenous retroviruses; Endogenous Retroviruses - immunology; Endogenous Retroviruses - metabolism; Endogenous Retroviruses - physiology; Envelope protein; Gene expression; Gene Expression Regulation, Viral; Gene Products, gag - genetics; Gene Products, gag - immunology; Gene Products, gag - metabolism; Genetic aspects; Genetic diversity; Genomes; HIV (Viruses); HIV Infections - immunology; HIV Infections - virology; HIV-1 - immunology; HIV-1 - isolation & purification; HIV-1 - physiology; HIV-2 - immunology; HIV-2 - isolation & purification; HIV-2 - physiology; Homology; Host-Pathogen Interactions; Human immunodeficiency virus 1; Human immunodeficiency virus 2; Humans; Hypotheses; Immunity, Cellular; Infection; Infections; Lymphocytes; Lymphocytes T; Molecular Sequence Data; Nucleotide sequence; Proteins; Retrovirus; Simian immunodeficiency virus; Simian Immunodeficiency Virus - immunology; Simian Immunodeficiency Virus - isolation & purification; Simian Immunodeficiency Virus - physiology; T cells; Transcription; Transcriptional Activation; Vaccines; vif Gene Products, Human Immunodeficiency Virus - physiology; Viral Envelope Proteins - genetics; Viral Envelope Proteins - immunology; Viral Envelope Proteins - metabolism; Virus Integration; Virus Internalization; Canada
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI64560

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.