title: Nonhuman TRIM5 Variants Enhance Recognition of HIV-1-Infected Cells by CD8+ T Cells.
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 nonhuman 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 nonimmunosuppressive analog of cyclosporine (CsA), sarcosine-3(4-methylbenzoate)-CsA (SmBz-CsA), we found a significant reduction in CD107a/MIP-1β 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 nonhuman TRIM5 variants in cellular immunity. We hypothesize that TRIM5 can couple innate viral sensing and CD8(+) T-cell activation to increase species barriers against retrovirus infection.
  
  
  
  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 nonhuman 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.
authors.affiliation: AIDS Research Institute, IrsiCaixa, Hospital Germans Trias i Pujol, Badalona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Jimenez-Moyano
authors.affiliation: AIDS Research Institute, IrsiCaixa, Hospital Germans Trias i Pujol, Badalona, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Ruiz
authors.affiliation: KwaZulu-Natal Research Institute for TB and HIV, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Henrik N
authors.initials: HN
authors.lastname: Kløverpris
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Rodriguez-Plata
authors.affiliation: AIDS Research Institute, IrsiCaixa, Hospital Germans Trias i Pujol, Badalona, Spain.
authors.forename: Ruth
authors.initials: R
authors.lastname: Peña
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Caroline
authors.initials: C
authors.lastname: Blondeau
authors.affiliation: The Wolfson Institute for Biomedical Research, University College London, United Kingdom.
authors.forename: David L
authors.initials: DL
authors.lastname: Selwood
authors.affiliation: AIDS Research Institute, IrsiCaixa, Hospital Germans Trias i Pujol, Badalona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Izquierdo-Useros
authors.affiliation: Sorbonne Universités, UPMC University Paris 6, INSERM U1135, CNRS ERL 8255, Center for Immunology and Microbial Infections-Paris, Paris, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Moris
authors.affiliation: AIDS Research Institute, IrsiCaixa, Hospital Germans Trias i Pujol, Badalona, Spain.
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.affiliation: Department of Paediatrics, University of Oxford, Oxford, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Goulder
authors.affiliation: Division of Infection and Immunity, University College London, London, United Kingdom.
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Towers
authors.affiliation: AIDS Research Institute, IrsiCaixa, Hospital Germans Trias i Pujol, Badalona, Spain jgarciaprado@irsicaixa.es.
authors.forename: Julia G
authors.initials: JG
authors.lastname: Prado
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D021984:Cyclophilin A / Q000378:metabolism*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008253:Macaca mulatta / Q000276:immunology*; D011506:Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
chemical_list: D011506:Proteins; C482587:TRIM5(alpha) protein, rhesus monkey; D044767:Ubiquitin-Protein Ligases; D021984:Cyclophilin A