HERV-K–specific T cells eliminate diverse HIV-1/2 and SIV primary isolates
R. Brad Jones, … , Douglas F. Nixon, Mario A. Ostrowski
R. Brad Jones, … , Douglas F. Nixon, Mario A. Ostrowski
Published November 12, 2012
Citation Information: J Clin Invest. 2012;122(12):4473-4489. https://doi.org/10.1172/JCI64560.
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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 1

HIV-1 infection results in the induction of HERV-K(HML-2) transcripts.

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HIV-1 infection results in the induction of HERV-K(HML-2) transcripts. (...
(A) CD4+ T cells were enriched from the PBMCs of HIV-1–uninfected individuals, activated, and then either infected with HIV-1 or maintained as mock-infected (uninfected) controls. Copy numbers of HERV-K(HML-2) and TBP RNA were determined using TaqMan-based qPCR by comparison to linearized plasmid standards. Data from an infection with the HIV-1 isolate 90TH_BK132, depicting the mean number HERV-K(HML-2) copies per copy TBP are shown. Quantitations were performed in triplicate, and error bars represent SEM. Also shown are levels of HIV-1 infection (% HIV-Gag+) at the indicated time points, as measured by flow cytometric staining for CD4 and HIV-Gag. Similar data were observed in cells from each of 4 donors tested and with each of the 2 primary HIV-1 isolates tested (90TH_BK132 and 99UG_A0848M1). (B) RNA from the sample analyzed in A was amplified using the MessageAmp Kit (Ambion). HERV-K(HML-2)-pol RNA was quantified by TaqMan qPCR and standardized to relative quantities of the housekeeping genes PP-1A, GAPDH, or ACTB determined by SYBR qPCR. Values are expressed using the following formula: arbitrary units = (standardized quantity)/(standardized quantity in uninfected 26-hour time point). uninf., uninfected; st., strain. (C) Representative absolute qPCR data depicting copies of spliced HERV-K(HML-2)-rec per copy TBP for cells from a single subject infected with the indicated HIV-1 viruses. Quantitations were performed in triplicate, and error bars represent SEM. Levels of HIV-1 infection corresponding to qPCR sampling points, as measured by flow cytometry are also shown.