Capsid Processing Requirements for Abrogation of Fv1 and Ref1 Restriction

Dodding, Mark P.; Bock, Michael; Yap, Melvyn W.; Stoye, Jonathan P.

doi:10.1128/jvi.79.16.10571-10577.2005

Cited by 45 publications

(46 citation statements)

References 35 publications

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“…An understanding of the 2A reaction mechanism requires definition of the C terminus of the upstream and N terminus of the downstream reaction products. In a number of cases, the first amino acid of the downstream product has been shown to be proline 19-or its equivalent in different 2A peptides (13,32,34,37,50). To complement these studies, the C terminus of the 2A upstream reaction product was determined.…”

Section: Resultsmentioning

confidence: 99%

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Site-Specific Release of Nascent Chains from Ribosomes at a Sense Codon

Doronina

Felipe

et al. 2008

Molecular and Cellular Biology

147

143

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Section: Resultsmentioning

confidence: 99%

“…The separation point is at the C terminus of 2A, with the first amino acid of the downstream product being proline (13,32,34,37,50). This residue, termed proline 19 herein, is the final amino acid of a conserved, functionally important motif, D(V/I)EXNPGP.…”

mentioning

confidence: 99%

Site-Specific Release of Nascent Chains from Ribosomes at a Sense Codon

Doronina

Felipe

et al. 2008

Molecular and Cellular Biology

147

143

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“…Optimal stability of the CA lattice and its timely uncoating have previously been proposed to be important for reverse transcription (28)(29)(30)(31)(32)(33)(34)(35). Nevertheless, higher-order CA structures must still exist in cells because the host restriction factor TRIM5 recognizes structural features that exist only in viral cores but not in individual CA monomers (36)(37)(38)(39). However, the presence of a conical core is likely not necessary for TRIM5 restriction, as a CA-NC cleavage mutant that does not form conical cores can efficiently saturate TRIM5 restriction (40), and TRIM5 can form lattices around hexameric CA-NC assemblies in vitro (41).…”

mentioning

confidence: 99%

Allosteric HIV-1 Integrase Inhibitors Lead to Premature Degradation of the Viral RNA Genome and Integrase in Target Cells

Madison

Lawson

Elliott

et al. 2017

J Virol

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Recent evidence indicates that inhibition of HIV-1 integrase (IN) binding to the viral RNA genome by allosteric integrase inhibitors (ALLINIs) or through mutations within IN yields aberrant particles in which the viral ribonucleoprotein complexes (vRNPs) are eccentrically localized outside the capsid lattice. These particles are noninfectious and are blocked at an early reverse transcription stage in target cells. However, the basis of this reverse transcription defect is unknown. Here, we show that the viral RNA genome and IN from ALLINI-treated virions are prematurely degraded in target cells, whereas reverse transcriptase remains active and stably associated with the capsid lattice. The aberrantly shaped cores in ALLINI-treated particles can efficiently saturate and be degraded by a restricting TRIM5 protein, indicating that they are still composed of capsid proteins arranged in a hexagonal lattice. Notably, the fates of viral core components follow a similar pattern in cells infected with eccentric particles generated by mutations within IN that inhibit its binding to the viral RNA genome. We propose that IN-RNA interactions allow packaging of both the viral RNA genome and IN within the protective capsid lattice to ensure subsequent reverse transcription and productive infection in target cells. Conversely, disruption of these interactions by ALLINIs or mutations in IN leads to premature degradation of both the viral RNA genome and IN, as well as the spatial separation of reverse transcriptase from the viral genome during early steps of infection.IMPORTANCE Recent evidence indicates that HIV-1 integrase (IN) plays a key role during particle maturation by binding to the viral RNA genome. Inhibition of IN-RNA interactions yields aberrant particles with the viral ribonucleoprotein complexes (vRNPs) eccentrically localized outside the conical capsid lattice. Although these particles contain all of the components necessary for reverse transcription, they are blocked at an early reverse transcription stage in target cells. To explain the basis of this defect, we tracked the fates of multiple viral components in infected cells. Here, we show that the viral RNA genome and IN in eccentric particles are prematurely degraded, whereas reverse transcriptase remains active and stably associated within the capsid lattice. We propose that IN-RNA interactions ensure the packaging of both vRNPs and IN within the protective capsid cores to facilitate subsequent reverse transcription and productive infection in target cells.KEYWORDS ALLINIs, capsid, HIV-1, integrase, maturation, protein-RNA interaction, RNA packaging, TRIM5, reverse transcriptase

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“…First, the viral determinants of susceptibility to restriction map to the capsid protein (14)(15)(16)(17). Second, when introduced into cells, assembled and proteolytically processed capsids of virus-like particles, but not monomeric capsid proteins expressed in the cells, can compete for the restriction factor(s) (14,16,18,19). Third, TRIMCyp is an HIV-1-restricting factor in owl monkeys consisting of the RBCC domains of TRIM5 fused with cyclophilin A, a known capsid ligand (14,(18)(19)(20)(21)(22)(23).…”

mentioning

confidence: 99%

“…Second, when introduced into cells, assembled and proteolytically processed capsids of virus-like particles, but not monomeric capsid proteins expressed in the cells, can compete for the restriction factor(s) (14,16,18,19). Third, TRIMCyp is an HIV-1-restricting factor in owl monkeys consisting of the RBCC domains of TRIM5 fused with cyclophilin A, a known capsid ligand (14,(18)(19)(20)(21)(22)(23). Finally, an association of TRIM5␣ hu with capsids prepared by detergent treatment of a restricted murine leukemia virus (MLV) has been observed (24).…”

mentioning

confidence: 99%

Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5α restriction factor

Stremlau

Perron

Lee

et al. 2006

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

656

889

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The host restriction factor TRIM5␣ mediates species-specific, early blocks to retrovirus infection; susceptibility to these blocks is determined by viral capsid sequences. Here we demonstrate that TRIM5␣ variants from Old World monkeys specifically associate with the HIV type 1 (HIV-1) capsid and that this interaction depends on the TRIM5␣ B30.2 domain. Human and New World monkey TRIM5␣ proteins associated less efficiently with the HIV-1 capsid, accounting for the lack of restriction in cells of these species. After infection, the expression of a restricting TRIM5␣ in the target cells correlated with a decrease in the amount of particulate capsid in the cytosol. In some cases, this loss of particulate capsid was accompanied by a detectable increase in soluble capsid protein.Inhibiting the proteasome did not abrogate restriction. Thus, TRIM5␣ restricts retroviral infection by specifically recognizing the capsid and promoting its rapid, premature disassembly.

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Capsid Processing Requirements for Abrogation of Fv1 and Ref1 Restriction

Cited by 45 publications

References 35 publications

Site-Specific Release of Nascent Chains from Ribosomes at a Sense Codon

Site-Specific Release of Nascent Chains from Ribosomes at a Sense Codon

Allosteric HIV-1 Integrase Inhibitors Lead to Premature Degradation of the Viral RNA Genome and Integrase in Target Cells

Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5α restriction factor

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