The Interferon Response Inhibits HIV Particle Production by Induction of TRIM22

Abstract

Treatment of human cells with Type 1 interferons restricts HIV replication. Here we report that the tripartite motif protein TRIM22 is a key mediator. We used transcriptional profiling to identify cellular genes that were induced by interferon treatment and identified TRIM22 as one of the most strongly up-regulated genes. We confirmed, as in previous studies, that TRIM22 over-expression inhibited HIV replication. To assess the role of TRIM22 expressed under natural inducing conditions, we compared the effects of interferon in cells depleted for TRIM22 using RNAi and found that HIV particle release was significantly increased in the knockdown, implying that TRIM22 acts as a natural antiviral effector. Further studies showed that TRIM22 inhibited budding of virus-like particles containing Gag only, indicating that Gag was the target of TRIM22. TRIM22 did not block the release of MLV or EIAV Gag particles. Inhibition was associated with diffuse cytoplasmic staining of HIV Gag rather than accumulation at the plasma membrane, suggesting TRIM22 disrupts proper trafficking. Mutational analyses of TRIM22 showed that the catalytic amino acids Cys15 and Cys18 of the RING domain are required for TRIM22 antiviral activity. These data disclose a pathway by which Type 1 interferons obstruct HIV replication.

TRIM22 E3 ubiquitin ligase activity is required to mediate antiviral activity against encephalomyocarditis virus

“…TRIM22 has been shown to interfere with HIV-1 infection by either LTR promoter repression (Tissot & Mechti, 1995), inhibition of viral replication (Bouazzaoui et al, 2006) or reduction of particle production (Barr et al, 2008). Interestingly, the C-terminal SPRY domain of TRIM proteins is proposed to be involved in protein-protein interactions and RNA binding (Hilton et al, 1998;Ponting et al, 1997).…”

“…TRIM22 (also known as Staf50) was first identified to be an IFN-induced human protein that represses transcription directed by the long terminal repeat (LTR) promoter region of human immunodeficiency virus type 1 (HIV-1) (Tissot & Mechti, 1995). Recently, TRIM22 has been reported to be a natural antiviral effector of both HIV-1 replication and particle production (Barr et al, 2008;Bouazzaoui et al, 2006). The effect of TRIM22 was abolished by mutation of amino acids Cys15 and Cys18 of its RING-finger domain, suggesting that functional ubiquitin ligase activity is required for TRIM22-mediated antiviral activities.…”

Determinants for the Rhesus Monkey TRIM5α-mediated Block of the Late Phase of HIV-1 Replication

“…The possible candidates include other TRIM family protein(s), such as TRIM22 or TRIM21, or a cellular protease. TRIM22 was recently identified to affect HIV-1 production through interaction with HIV-1 Gag polyprotein, and like TRIM5␣rh-mediated late restriction, disruption of the RING motif ablates the late restriction activity of TRIM22 (15). Moreover, the type I interferon-responsive TRIM5 and TRIM22 genes share the enhancer region, suggesting a similar transcriptional regulation of the two proteins (16,20).…”

“…These data indicate that a RING domain is required for the efficient interaction with HIV-1 Gag polyproteins. The block of HIV-1 entry appears to occur independently of the ubiquitin/proteasome system during the TRIM5␣rh-mediated post-entry restriction (9,14), although more recent studies have demonstrated that proteasome inhibitors can partially relieve the TRIM5␣-dependent inhibition of reverse transcription without affecting the restriction of HIV-1 nuclear entry (2,15). We examined the influence of proteasome inhibitors on the late restriction.…”

“…These observations suggest the block of HIV-1 entry occurs independently of the ubiquitin/proteasome system. More recent studies, however, have demonstrated that proteasome inhibitors can relieve the TRIM5␣-dependent inhibition of reverse transcription without impairing the block of HIV-1 nuclear entry (2,15). Moreover, TRIM5␣ is rapidly degraded in cells exposed to a restriction-sensitive retrovirus, suggesting a role of proteasomal degradation in the restriction (5).…”