Preclinical Assessment of Mutant Human TRIM5α as an Anti-HIV-1 Transgene

Jung, Ulrike; Urak, Kevin; Veillette, Maxime; Nepveu-Traversy, Marie-Édith; Pham, Quang Toan; Hamel, Sébastien; Rossi, John J.; Berthoux, Lionel

doi:10.1089/hum.2015.059

Cited by 22 publications

(17 citation statements)

References 110 publications

(156 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The function of TRIM5 proteins as restriction factors and pattern recognition receptors ( 10 ), together with the function described here as enhancers of HIV-1 CD8 + T-cell recognition, make them good candidates for novel therapeutic strategies against HIV-1. Such therapies could target the generation of novel gene therapy vectors, where promising results have already been obtained ( 41 , 42 ), or small molecules that mimic the function of TRIM5 proteins. In this context, TRIM5-based gene therapy vectors will have an additional protective immune function through induction of antiviral CD8 + T-cell responses.…”

Section: Discussionmentioning

confidence: 99%

Nonhuman TRIM5 Variants Enhance Recognition of HIV-1-Infected Cells by CD8 ⁺ T Cells

Jiménez-Moyano

Ruiz

Kløverpris

et al. 2016

J Virol

View full text Add to dashboard Cite

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.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 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.

show abstract

Section: Discussionmentioning

confidence: 99%

Nonhuman TRIM5 Variants Enhance Recognition of HIV-1-Infected Cells by CD8 ⁺ T Cells

Jiménez-Moyano

Ruiz

Kløverpris

et al. 2016

J Virol

View full text Add to dashboard Cite

show abstract

“…The presence of K63-linked ubiquitin chains has been proposed to be important for AP-1 and NF-κB transactivation [ 26 , 28 ]. Activation of NF-κB and AP-1 by TRIM5α is triggered by contact with a restriction sensitive virus [26] or by transient transfection of TRIM5α [ 25 , 26 , 29 , 30 ], but not by stable lentiviral transduction [31] .…”

Section: Introductionmentioning

confidence: 99%

A putative SUMO interacting motif in the B30.2/SPRY domain of rhesus macaque TRIM5α important for NF-κB/AP-1 signaling and HIV-1 restriction

Nepveu-Traversy

Demogines

Fricke

et al. 2016

Heliyon

Self Cite

View full text Add to dashboard Cite

TRIM5α from the rhesus macaque (TRIM5αRh) is a restriction factor that shows strong activity against HIV-1. TRIM5αRh binds specifically to HIV-1 capsid (CA) through its B30.2/PRYSPRY domain shortly after entry of the virus into the cytoplasm. Recently, three putative SUMO interacting motifs (SIMs) have been identified in the PRYSPRY domain of human and macaque TRIM5α. However, structural modeling of this domain suggested that two of them were buried in the hydrophobic core of the protein, implying that interaction with SUMO was implausible, while the third one was not relevant to restriction. In light of these results, we re-analyzed the TRIM5αRh PRYSPRY sequence and identified an additional putative SIM (435VIIC438) which we named SIM4. This motif is exposed at the surface of the PRYSPRY domain, allowing potential interactions with SUMO or SUMOylated proteins. Introducing a double mutation in SIM4 (V435K, I436K) did not alter stability, unlike mutations in SIM1. SIM4-mutated TRIM5αRh failed to bind HIV-1CA and lost the ability to restrict this virus. Accordingly, SIM4 undergoes significant variation among primates and substituting this motif with naturally occurring SIM4 variants affected HIV-1 restriction by TRIM5αRh, suggesting a direct role in capsid recognition. Interestingly, SIM4-mutated TRIM5αRh also failed to activate NF-κB and AP-1-mediated transcription. Although there is no direct evidence that SIM4 is involved in direct interaction with SUMO or a SUMOylated protein, mutating this motif strongly reduced co-localization of TRIM5αRh with SUMO-1 and with PML, a SUMOylated nuclear protein. In conclusion, this new putative SIM is crucial for both direct interaction with incoming capsids and for NF-κB/AP-1 signaling. We speculate that the latter function is mediated by interactions of SIM4 with a SUMOylated protein involved in the NF-κB/AP-1 signaling pathways.

show abstract

“…46 In contrast, some simian orthologs retain anti-HIV activity, enabling the identification of mutations that can be introduced into the human proteins to restore anti-HIV activity. [47][48][49][50][51] Studies of natural polymorphisms also suggest that restriction factor variants can affect the course of HIV infection in vivo, 52 further supporting a strategy of genetically modifying restriction factors to combat HIV. Beyond restriction factors, other host protein polymorphisms have been linked to HIV disease progression, including the major histocompatibility complex region.…”

Section: Ccr5 Disruption In Hspcsmentioning

confidence: 96%

Clinical Applications of Genome Editing to HIV Cure

Wang

Cannon

2016

AIDS Patient Care and STDs

View full text Add to dashboard Cite

show abstract

Preclinical Assessment of Mutant Human TRIM5α as an Anti-HIV-1 Transgene

Cited by 22 publications

References 110 publications

Nonhuman TRIM5 Variants Enhance Recognition of HIV-1-Infected Cells by CD8 ⁺ T Cells

Nonhuman TRIM5 Variants Enhance Recognition of HIV-1-Infected Cells by CD8 ⁺ T Cells

A putative SUMO interacting motif in the B30.2/SPRY domain of rhesus macaque TRIM5α important for NF-κB/AP-1 signaling and HIV-1 restriction

Clinical Applications of Genome Editing to HIV Cure

Contact Info

Product

Resources

About

Preclinical Assessment of Mutant Human TRIM5α as an Anti-HIV-1 Transgene

Cited by 22 publications

References 110 publications

Nonhuman TRIM5 Variants Enhance Recognition of HIV-1-Infected Cells by CD8 + T Cells

Nonhuman TRIM5 Variants Enhance Recognition of HIV-1-Infected Cells by CD8 + T Cells

A putative SUMO interacting motif in the B30.2/SPRY domain of rhesus macaque TRIM5α important for NF-κB/AP-1 signaling and HIV-1 restriction

Clinical Applications of Genome Editing to HIV Cure

Contact Info

Product

Resources

About

Nonhuman TRIM5 Variants Enhance Recognition of HIV-1-Infected Cells by CD8 ⁺ T Cells

Nonhuman TRIM5 Variants Enhance Recognition of HIV-1-Infected Cells by CD8 ⁺ T Cells