RING Domain Mutations Uncouple TRIM5α Restriction of HIV-1 from Inhibition of Reverse Transcription and Acceleration of Uncoating

Roa, Amanda; Hayashi, Fumiaki; Yang, Yang; Lienlaf, Maritza; Zhou, Jing; Shi, Jiong; Watanabe, Satoru; Kigawa, T.; Yokoyama, Shigeyuki; Aiken, Christopher; Díaz-Griffero, Felipe

doi:10.1128/jvi.05811-11

Cited by 77 publications

(81 citation statements)

References 60 publications

(113 reference statements)

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“…Viral capsids are thought to shield incoming retroviral replication complexes from cellular sensors of infection. The t 1/2 for MLV attachment through completion of reverse transcription is ∼3-4 h (41), and capsid disassembly is believed to occur either simultaneously with or just before reverse transcription (42,43). Thus, the less stable glyco-Gag mutant capsid could allow intracellular sensors to more readily sense viral RNA or DNA.…”

Section: Apobec3 Restricts Endogenous Reverse Transcription Of Glyco-gagmentioning

confidence: 99%

Murine leukemia virus glycosylated Gag blocks apolipoprotein B editing complex 3 and cytosolic sensor access to the reverse transcription complex

Stavrou

Nitta

Kotla

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

194

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Pathogenic retroviruses have evolved multiple means for evading host restriction factors such as apolipoprotein B editing complex (APOBEC3) proteins. Here, we show that murine leukemia virus (MLV) has a unique means of counteracting APOBEC3 and other cytosolic sensors of viral nucleic acid. Using virus isolated from infected WT and APOBEC3 KO mice, we demonstrate that the MLV glycosylated Gag protein (glyco-Gag) enhances viral core stability. Moreover, in vitro endogenous reverse transcription reactions of the glyco-Gag mutant virus were substantially inhibited compared with WT virus, but only in the presence of APOBEC3. Thus, glyco-Gag rendered the reverse transcription complex in the viral core resistant to APOBEC3. Glyco-Gag in the virion also rendered MLV resistant to other cytosolic sensors of viral reverse transcription products in newly infected cells. Strikingly, glycoGag mutant virus reverted to glyco-Gag-containing virus only in WT and not APOBEC3 KO mice, indicating that counteracting APOBEC3 is the major function of glyco-Gag. Thus, in contrast to the HIV viral infectivity factor protein, which prevents APOBEC3 packaging in the virion, the MLV glyco-Gag protein uses a unique mechanism to counteract the antiviral action of APOBEC3 in vivonamely, protecting the reverse transcription complex in viral cores from APOBEC3. These data suggest that capsid integrity may play a critical role in virus resistance to intrinsic cellular antiviral resistance factors that act at the early stages of infection.intrinsic immunity | trex1 | virus restriction factors

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Section: Apobec3 Restricts Endogenous Reverse Transcription Of Glyco-gagmentioning

confidence: 99%

Murine leukemia virus glycosylated Gag blocks apolipoprotein B editing complex 3 and cytosolic sensor access to the reverse transcription complex

Stavrou

Nitta

Kotla

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

194

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“…In the second step, TRIM5␣ induces the abortive disassembly of the viral capsid core and prevents the accumulation of reverse transcription (RT) products. The latter step requires the E3 ligase activity of the TRIM5␣ RING domain and is sensitive to proteasome inhibitors, although restriction of infection remains potent in both cases (9,(21)(22)(23)(24). Additionally, the presence of restriction-sensitive virus triggers the degradation of TRIM5␣, and this degradation is also sensitive to proteasome inhibitors (25).…”

mentioning

confidence: 99%

“…Numerous studies have found that retroviral restriction by TRIM5␣ proteins occurs by a two-step mechanism (21)(22)(23)(24)(25). In the first step, which is sufficient to prevent infection, TRIM5␣ recognizes the viral capsid via its C-terminal PRY/SPRY domain (or CypA in the case of TRIM-Cyp).…”

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confidence: 99%

TRIM5α Degradation via Autophagy Is Not Required for Retroviral Restriction

Imam

Talley

Nelson

et al. 2016

J Virol

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TRIM5␣ is an interferon-inducible retroviral restriction factor that prevents infection by inducing the abortive disassembly of capsid cores recognized by its C-terminal PRY/SPRY domain. The mechanism by which TRIM5␣ mediates the disassembly of viral cores is poorly understood. Previous studies demonstrated that proteasome inhibitors abrogate the ability of TRIM5␣ to induce premature core disassembly and prevent reverse transcription; however, viral infection is still inhibited, indicating that the proteasome is partially involved in the restriction process. Alternatively, we and others have observed that TRIM5␣ associates with proteins involved in autophagic degradation pathways, and one recent study found that autophagic degradation is required for the restriction of retroviruses by TRIM5␣. Here, we show that TRIM5␣ is basally degraded via autophagy in the absence of restriction-sensitive virus. We observe that the autophagy markers LC3b and lysosome-associated membrane protein 2A (LAMP2A) localize to a subset of TRIM5␣ cytoplasmic bodies, and inhibition of lysosomal degradation with bafilomycin A1 increases this association. To test the requirement for macroautophagy in restriction, we examined the ability of TRIM5␣ to restrict retroviral infection in cells depleted of the autophagic mediators ATG5, Beclin1, and p62. In all cases, restriction of retroviruses by human TRIM5␣, rhesus macaque TRIM5␣, and owl monkey TRIM-Cyp remained potent in cells depleted of these autophagic effectors by small interfering RNA (siRNA) knockdown or clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 genome editing. Collectively, these results are consistent with observations that the turnover of TRIM5␣ proteins is sensitive to autophagy inhibition; however, the data presented here do not support observations that the inhibition of autophagy abrogates retroviral restriction by TRIM5 proteins. IMPORTANCERestriction factors are a class of proteins that inhibit viral replication. Following fusion of a retrovirus with a host cell membrane, the retroviral capsid is released into the cytoplasm of the target cell. TRIM5␣ inhibits retroviral infection by promoting the abortive disassembly of incoming retroviral capsid cores; as a result, the retroviral genome is unable to traffic to the nucleus, and the viral life cycle is extinguished. In the process of restriction, TRIM5␣ itself is degraded by the proteasome. However, in the present study, we have shown that in the absence of a restriction-sensitive virus, TRIM5␣ is degraded by both proteasomal and autophagic degradation pathways. Notably, we observed that restriction of retroviruses by TRIM5␣ does not require autophagic machinery. These data indicate that the effector functions of TRIM5␣ can be separated from its degradation and may have further implications for understanding the mechanisms of other TRIM family members.

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“…As shown in Figure 2B, BI-2 and PF74 did not affect the stability of the HIV-1 core bearing the change T107N. These results suggested that the ability , and used to perform the fate of the capsid assay 12 hours post-infection, as described [9,11]. Briefly, HIV-1 infected cells were used to prepare post-nuclear supernatants that were layered onto a 50% sucrose cushion to separate soluble from pelletable HIV-1 capsids.…”

Section: Bi-2 Destabilizes the Hiv-1 Core During Infectionmentioning

confidence: 99%

“…For this purpose, we challenged Cf2Th cells with HIV-1-GFP in the presence of 50 μM BI-2 and performed the fate of the capsid 12 hours post-infection, as previously described [9][10][11]. As shown in Figure 2A, the use of BI-2 destabilized the HIV-1 core during infection when compared with the DMSO control.…”

Section: Bi-2 Destabilizes the Hiv-1 Core During Infectionmentioning

confidence: 99%

BI-2 destabilizes HIV-1 cores during infection and Prevents Binding of CPSF6 to the HIV-1 Capsid

et al. 2014

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Background: The recently discovered small-molecule BI-2 potently blocks HIV-1 infection. BI-2 binds to the N-terminal domain of HIV-1 capsid. BI-2 utilizes the same capsid pocket used by the small molecule PF74. Although both drugs bind to the same pocket, it has been proposed that BI-2 uses a different mechanism to block HIV-1 infection when compared to PF74. Findings: This work demonstrates that BI-2 destabilizes the HIV-1 core during infection, and prevents the binding of the cellular factor CPSF6 to the HIV-1 core. Conclusions: Overall this short-form paper suggests that BI-2 is using a similar mechanism to the one used by PF74 to block HIV-1 infection.

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RING Domain Mutations Uncouple TRIM5α Restriction of HIV-1 from Inhibition of Reverse Transcription and Acceleration of Uncoating

Cited by 77 publications

References 60 publications

Murine leukemia virus glycosylated Gag blocks apolipoprotein B editing complex 3 and cytosolic sensor access to the reverse transcription complex

Murine leukemia virus glycosylated Gag blocks apolipoprotein B editing complex 3 and cytosolic sensor access to the reverse transcription complex

TRIM5α Degradation via Autophagy Is Not Required for Retroviral Restriction

BI-2 destabilizes HIV-1 cores during infection and Prevents Binding of CPSF6 to the HIV-1 Capsid

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