Activation of NF-κB induced by TRIMCyp showing a discrepancy between owl monkey and northern pig-tailed macaque

Area of Science:

• Immunology
• Virology
• Primate Genetics

Background:

• TRIMCyp, derived from cyclophilin A insertion into TRIM5, is found in Old World monkeys (OWM).
• Owl monkey TRIMCyp (omTRIMCyp) inhibits HIV-1, but most OWM TRIMCyps do not, with their immunoregulation roles unclear.
• The functional differences in TRIMCyp's antiviral and immune-modulating activities between species are not well understood.

Purpose of the Study:

• To compare the immune-activating functions of omTRIMCyp and northern pig-tailed macaque TRIMCyp (npmTRIMCyp).
• To elucidate the molecular mechanisms underlying the differential activation of immune pathways by these TRIMCyp variants.
• To understand the implications of these functional differences for HIV-1 infection and latency in macaques.

Main Methods:

• Comparative analysis of NF-κB, AP-1, and IFN-β activation by omTRIMCyp and npmTRIMCyp.
• Investigation of the roles of Cyclophilin A (CypA) and RBCC domains in omTRIMCyp-mediated immune activation.
• Assessment of IκBα phosphorylation and ubiquitination activity differences between omTRIMCyp and npmTRIMCyp.
• Evaluation of TRIMCyp interaction with viral capsid and its effect on HIV-1 susceptibility.

Main Results:

• omTRIMCyp dose-dependently induces NF-κB, AP-1, and IFN-β, while npmTRIMCyp shows moderate AP-1 and IFN-β enhancement but no NF-κB activation.
• The CypA domain is crucial for omTRIMCyp-induced NF-κB activation, with RBCC domains providing a synergistic effect.
• npmTRIMCyp exhibits significantly lower IκBα phosphorylation and ubiquitination activity compared to omTRIMCyp.
• npmTRIMCyp does not interact with the viral capsid, leading to HIV-1 susceptibility.

Conclusions:

• omTRIMCyp possesses potent antiviral and immune-stimulating properties via NF-κB and other pathways.
• npmTRIMCyp's inability to activate NF-κB and interact with viral capsids suggests a role in maintaining HIV-1 latency in macaques.
• The differential functional activities of TRIMCyp variants highlight species-specific adaptations in primate antiviral defense mechanisms.