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Non-human TRIM5 variants enhance recognition of HIV-1-infected cells by CD8+ T cells

Jimenez, E; Ruiz, A; Kløverpris, HN; Rodriguez-Plata, MT; Peña, R; Blondeau, C; Selwood, DL; ... Prado, JG; + view all (2016) Non-human TRIM5 variants enhance recognition of HIV-1-infected cells by CD8+ T cells. Journal of Virology , 90 (19) pp. 8552-8562. 10.1128/JVI.00819-16. Green open access

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Abstract

Tripartite motif-containing protein 5 (TRIM5) restricts human immunodeficiency virus type-1 (HIV-1) in a species-specific manner by uncoating viral particles while activating early innate responses. Although the contribution of TRIM5 proteins to cellular immunity has not yet been studied, their interactions with the incoming viral capsid and the cellular proteasome led us to hypothesize a role for them. Here, we investigate whether the expression of two non-human TRIM5 orthologs, rhesus TRIM5α (RhT5) and TRIM-cyclophilin A (TCyp), both of which are potent restrictors of HIV-1, could enhance immune recognition of infected cells by CD8+ T cells. We illustrate how TRIM5 restriction improves CD8+ T cell-mediated HIV-1 inhibition. Moreover, when TRIM5 activity was blocked by the non-immunosuppressive analog of cyclosporin A, SmBz-CsA, we found a significant reduction in CD107a/MIP1β expression in HIV-1-specific CD8+ T cells. This finding underscores the direct link between TRIM5 restriction and activation of CD8+ T-cell responses. Interestingly, cells expressing RhT5 induced stronger CD8+ T-cell responses through the specific recognition of the HIV-1 capsid by the immune system. The underlying mechanism of this process may involve TRIM5-specific capsid recruitment to cellular proteasomes and increase peptide availability for loading and presentation of HLA class I antigens. In summary, we identified a novel function for non-human TRIM5 variants in cellular immunity. We hypothesise that TRIM5 can couple innate viral sensing and CD8+ T-cell activation to increase species barriers against retrovirus infection. IMPORTANCE: New therapeutics to tackle HIV-1 infection should aim to combine rapid innate viral sensing and cellular immune recognition. Such strategies could prevent seeding of the viral reservoir and the immune damage that occurs during acute infection. The non-human TRIM5 variants, rhesus TRIM5α (RhT5) and TRIM-cyclophilin A (TCyp), are attractive candidates owing to their potency in sensing HIV-1 and blocking its activity. Here, we show that expression of RhT5 and TCyp in HIV-1-infected cells improves CD8+ T cell-mediated inhibition through the direct activation of HIV-1-specific CD8+ T-cell responses. We found that the potency in CD8+ activation was stronger for RhT5 variants and capsid-specific CD8+ T-cells in a mechanism that relies on TRIM5-dependent particle recruitment to cellular proteasomes. This novel mechanism couples innate viral sensing with cellular immunity in a single protein and could be exploited to develop innovative therapeutics for control of HIV-1 infection.

Type: Article
Title: Non-human TRIM5 variants enhance recognition of HIV-1-infected cells by CD8+ T cells
Open access status: An open access version is available from UCL Discovery
DOI: 10.1128/JVI.00819-16
Publisher version: http://dx.doi.org/10.1128/JVI.00819-16
Language: English
Additional information: Copyright © 2016 Jimenez et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. Further details about CC BY licenses are available at http://creativecommons.org/licenses/by/4.0
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research
URI: https://discovery.ucl.ac.uk/id/eprint/1506376
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