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.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.

Latent HIV reservoirs exhibit inherent resistance to elimination by CD8+ T cells

“…The first relates to immunoevasion mediated by HIV Nef, which acts to downregulate MHC-I on infected cells, thereby diminishing recognition by CD8 + T cells (61). In productive HIV replication, Nef immunoevasion is likely limited -to some extent -by the early presentation of antigen from incoming virions prior to Nef-mediated MHC-I downregulation (within 2-6 hours of infection) (62)(63)(64)(65)(66)(67)(68)(69)(70). In the setting of reactivation from latency there is no parallel to this eclipse phase, and the expression of late gene products (such as Gag) will occur only after MHC-I downregulation occurs.…”

Delayed disease progression in HIV-2: the importance of TRIM5α and the retroviral capsid

“…This late restriction is a saturable process, as increased virion production may overwhelm it [23]. (d) We hypothesize that enhanced proteasomal processing selects for epitopes which are associated with protective gag-specific CD8 + T cell responses presented on human leucocyte antigen (HLA) class I molecules [32,33]. Additional anti-retroviral mechanisms include that TRIM5 binding to the incoming capsid prevents nuclear entry via nucleoporin channels [24] and also stimulates transforming growth factor (TGF) beta-activated kinase 1 (TAK-1) phosphorylation, which activates the The RTC is then recruited to the cellular proteasome for degradation.…”

“…Multiple lines of evidence indicate that TRIM5α may, soon after initiating viral uncoating, target the viral capsid for proteasomal degradation [32]. The interaction between the viral capsid, host restriction factors and the cellular immune response may be central to maintaining durable control of viral replication in HIV-2 infection.…”

“…Additional anti-retroviral mechanisms include that TRIM5 binding to the incoming capsid prevents nuclear entry via nucleoporin channels [24] and also stimulates transforming growth factor (TGF) beta-activated kinase 1 (TAK-1) phosphorylation, which activates the The RTC is then recruited to the cellular proteasome for degradation. (d) We hypothesize that enhanced proteasomal processing selects for epitopes which are associated with protective gag-specific CD8 + T cell responses presented on human leucocyte antigen (HLA) class I molecules [32,33]. nuclear factor kappa B (NF-κB) transcription pathway [25].…”

“…The interaction between the viral capsid, host restriction factors and the cellular immune response may be central to maintaining durable control of viral replication in HIV-2 infection. Multiple lines of evidence indicate that TRIM5α may, soon after initiating viral uncoating, target the viral capsid for proteasomal degradation [32]. During this process, HIV-2 capsids enriched in proline residues may favour the efficient processing of CTL epitopes that are associated with a long-lasting, protective gag-specific CTL response.…”