HERV-K–specific T cells eliminate diverse HIV-1/2 and SIV primary isolates
R. Brad Jones, Keith E. Garrison, Shariq Mujib, Vesna Mihajlovic, Nasra Aidarus, Diana V. Hunter, Eric Martin, Vivek M. John, Wei Zhan, Nabil F. Faruk, Gabor Gyenes, Neil C. Sheppard, Ingrid M. Priumboom-Brees, David A. Goodwin, Lianchun Chen, Melanie Rieger, Sophie Muscat-King, Peter T. Loudon, Cole Stanley, Sara J. Holditch, Jessica C. Wong, Kiera Clayton, Erick Duan, Haihan Song, Yang Xu, Devi SenGupta, Ravi Tandon, Jonah B. Sacha, Mark A. Brockman, Erika Benko, Colin Kovacs, Douglas F. Nixon, Mario A. Ostrowski
R. Brad Jones, Keith E. Garrison, Shariq Mujib, Vesna Mihajlovic, Nasra Aidarus, Diana V. Hunter, Eric Martin, Vivek M. John, Wei Zhan, Nabil F. Faruk, Gabor Gyenes, Neil C. Sheppard, Ingrid M. Priumboom-Brees, David A. Goodwin, Lianchun Chen, Melanie Rieger, Sophie Muscat-King, Peter T. Loudon, Cole Stanley, Sara J. Holditch, Jessica C. Wong, Kiera Clayton, Erick Duan, Haihan Song, Yang Xu, Devi SenGupta, Ravi Tandon, Jonah B. Sacha, Mark A. Brockman, Erika Benko, Colin Kovacs, Douglas F. Nixon, Mario A. Ostrowski
View: Text | PDF
Research Article AIDS/HIV

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

R. Brad Jones, Keith E. Garrison, Shariq Mujib, Vesna Mihajlovic, Nasra Aidarus, Diana V. Hunter, Eric Martin, Vivek M. John, Wei Zhan, Nabil F. Faruk, Gabor Gyenes, Neil C. Sheppard, Ingrid M. Priumboom-Brees, David A. Goodwin, Lianchun Chen, Melanie Rieger, Sophie Muscat-King, Peter T. Loudon, Cole Stanley, Sara J. Holditch, Jessica C. Wong, Kiera Clayton, Erick Duan, Haihan Song, Yang Xu, Devi SenGupta, Ravi Tandon, Jonah B. Sacha, Mark A. Brockman, Erika Benko, Colin Kovacs, Douglas F. Nixon, Mario A. Ostrowski

×

Figure 11

Recognition of HIV-1–infected cells by additional HERV-K(HML-2)–specific lines and clones.

Options: View larger image (or click on image) Download as PowerPoint
Recognition of HIV-1–infected cells by additional HERV-K(HML-2)–specific...
HIV-1-Gag–, HERV-K-Gag–, and HERV-K-Env–specific CD8+ T cell lines were established by a 9-day coculture of PBMCs with autologous mature DCs that had been transfected with codon-optimized mRNA encoding the corresponding antigen. (A) Expanded cell lines were cocultured with autologous CD4+ T cells that had been transfected with mRNA or maintained as a mock transfection control or had been infected with the primary isolate of HIV-1 J3222 or maintained as a mock-infected control. Shown are flow cytometry data, gated on the CD8+ lymphocyte population. (B) DC-expanded cell lines were plated at limiting dilution on irradiated feeder cells, then screened for antigen specificity by coculture with autologous BLCLs that had been transfected with the indicated mRNAs. Shown are IFN-γ ELISPOT data for 1 clone derived from the HERV-K(HML-2)-Gag expansion, exhibiting recognition of gag transfected BLCLs. (C) The HERV-K(HML-2)-Gag–specific CD8+ T cell clone from B was reexpanded. Shown are flow cytometry data, gated on CD8+ lymphocytes, for HERV-K(HML-2)–specific T cell clones cocultured for 6 hours with autologous BLCLs that had been transfected with GFP (negative control) or HERV-K(HML-2)-Gag encoding mRNA (top panel); no targets or autologous CD4+ T cells that had been infected with HIV-1-90TH_BK132 or mock infected (middle panel); or autologous HIV-1-99UG_A0848M1–infected CD4+ T cells in the presence of either an anti–MHC-I blocking antibody or an isotype control (bottom panel). Panels in C present results from 3 separate experiments performed during the same week, with the same expansion of clones. (A and C) Numbers represent percentages of CD107a+ cells.