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
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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

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Figure 6

Induction of HERV-K(HML-2)-Env antigen expression requires entry, reverse transcription, and integration of HIV-1 and is Vif dependent.

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Induction of HERV-K(HML-2)-Env antigen expression requires entry, revers...
(A) Primary CD4+ T cells from subject OM9 were treated with 1 μM each of efavirenz, nevirapine, integrase inhibitor 118-D-24, with 10 μg/ml of T20, or with a combination of each of these drugs (ARV Mix) throughout a 16-hour exposure to HIV-1 90TH_BK132 and then cocultured with the HERV-K(HML-2)-Env–specific T cell clone. Flow cytometry data comparing the frequencies of CD107a-IFN-γ dual-positive clone cell populations in response to these target cells are shown. Levels of HIV-1 infection were assessed by intracellular staining for Gag. (B) Activated CD4+ T cells from subject OM9 were infected with HIV-1 YU-2 or YU-2ΔVif for 16 hours or were maintained as mock infection controls and then cocultured with the indicated T cell clones. Summary data from 4 independent replicates are shown. Symbols represent individual replicates, and horizontal bars indicate the means. P values were calculated using Student’s t test. (C and D) Activated CD4+ T cells from subject OM9 were transfected with mRNA encoding EGFP, HIV-1-gag, and HIV-1-vif (from primary isolate ELI) or mock transfected and then cocultured with the indicated T cell clones. (C) Shown are flow cytometry data from a representative experiment, gated on CD8+ clone cells. Numbers represent percentages of CD107a+ cells. (D) Western blot depicting levels of APOBEC3G and HIV-1-Vif expression compared with a tubulin loading control in CD4+ T cells that had been infected with HIV-1-90TH_BK132, maintained as an uninfected control, mock electroporated (no RNA), or electroporated with vif mRNA. Samples were run at 1:1 (×1), 1:5 (×5), and 1:25 (×25) dilutions.