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. HolditchJessica C. Wong, Kiera Clayton, Erick Duan, Haihan Song, Yang Xu, Devi SenGupta, Ravi Tandon, Jonah Sacha, Mark A. Brockman, Erika Benko, Colin Kovacs, Douglas F. Nixon, Mario A. Ostrowski

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)4473-4489
Number of pages17
JournalJournal of Clinical Investigation
Volume122
Issue number12
DOIs
StatePublished - Dec 3 2012

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HIV-2
HIV-1
T-Lymphocytes
env Gene Products
Endogenous Retroviruses
gag Gene Products
AIDS Vaccines
Human Genome
Retroviridae
Cellular Immunity
HIV Infections
Vaccines
Clone Cells

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Jones, R. B., Garrison, K. E., Mujib, S., Mihajlovic, V., Aidarus, N., Hunter, D. V., ... Ostrowski, M. A. (2012). HERV-K-specific T cells eliminate diverse HIV-1/2 and SIV primary isolates. Journal of Clinical Investigation, 122(12), 4473-4489. https://doi.org/10.1172/JCI64560

HERV-K-specific T cells eliminate diverse HIV-1/2 and SIV primary isolates. / 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; Brockman, Mark A.; Benko, Erika; Kovacs, Colin; Nixon, Douglas F.; Ostrowski, Mario A.

In: Journal of Clinical Investigation, Vol. 122, No. 12, 03.12.2012, p. 4473-4489.

Research output: Contribution to journalArticle

Jones, RB, Garrison, KE, Mujib, S, Mihajlovic, V, Aidarus, N, Hunter, DV, Martin, E, John, VM, Zhan, W, Faruk, NF, Gyenes, G, Sheppard, NC, Priumboom-Brees, IM, Goodwin, DA, Chen, L, Rieger, M, Muscat-King, S, Loudon, PT, Stanley, C, Holditch, SJ, Wong, JC, Clayton, K, Duan, E, Song, H, Xu, Y, SenGupta, D, Tandon, R, Sacha, J, Brockman, MA, Benko, E, Kovacs, C, Nixon, DF & Ostrowski, MA 2012, 'HERV-K-specific T cells eliminate diverse HIV-1/2 and SIV primary isolates', Journal of Clinical Investigation, vol. 122, no. 12, pp. 4473-4489. https://doi.org/10.1172/JCI64560
Jones RB, Garrison KE, Mujib S, Mihajlovic V, Aidarus N, Hunter DV et al. HERV-K-specific T cells eliminate diverse HIV-1/2 and SIV primary isolates. Journal of Clinical Investigation. 2012 Dec 3;122(12):4473-4489. https://doi.org/10.1172/JCI64560
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 ; Brockman, Mark A. ; Benko, Erika ; Kovacs, Colin ; Nixon, Douglas F. ; Ostrowski, Mario A. / HERV-K-specific T cells eliminate diverse HIV-1/2 and SIV primary isolates. In: Journal of Clinical Investigation. 2012 ; Vol. 122, No. 12. pp. 4473-4489.
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T1 - HERV-K-specific T cells eliminate diverse HIV-1/2 and SIV primary isolates

AU - Jones, R. Brad

AU - Garrison, Keith E.

AU - Mujib, Shariq

AU - Mihajlovic, Vesna

AU - Aidarus, Nasra

AU - Hunter, Diana V.

AU - Martin, Eric

AU - John, Vivek M.

AU - Zhan, Wei

AU - Faruk, Nabil F.

AU - Gyenes, Gabor

AU - Sheppard, Neil C.

AU - Priumboom-Brees, Ingrid M.

AU - Goodwin, David A.

AU - Chen, Lianchun

AU - Rieger, Melanie

AU - Muscat-King, Sophie

AU - Loudon, Peter T.

AU - Stanley, Cole

AU - Holditch, Sara J.

AU - Wong, Jessica C.

AU - Clayton, Kiera

AU - Duan, Erick

AU - Song, Haihan

AU - Xu, Yang

AU - SenGupta, Devi

AU - Tandon, Ravi

AU - Sacha, Jonah

AU - Brockman, Mark A.

AU - Benko, Erika

AU - Kovacs, Colin

AU - Nixon, Douglas F.

AU - Ostrowski, Mario A.

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N2 - 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.

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