scholarly journals Primate TRIM5 proteins form hexagonal nets on HIV-1 capsids

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Yen-Li Li ◽  
Viswanathan Chandrasekaran ◽  
Stephen D Carter ◽  
Cora L Woodward ◽  
Devin E Christensen ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Reverse Transcription ◽  
Cyclophilin A ◽  
Restriction Factors ◽  
Viral Capsids ◽  
Ring Domains ◽  
Conformational Plasticity ◽  
Retroviral Infections ◽  
Hiv 1 ◽  
Terminal Domains

TRIM5 proteins are restriction factors that block retroviral infections by binding viral capsids and preventing reverse transcription. Capsid recognition is mediated by C-terminal domains on TRIM5α (SPRY) or TRIMCyp (cyclophilin A), which interact weakly with capsids. Efficient capsid recognition also requires the conserved N-terminal tripartite motifs (TRIM), which mediate oligomerization and create avidity effects. To characterize how TRIM5 proteins recognize viral capsids, we developed methods for isolating native recombinant TRIM5 proteins and purifying stable HIV-1 capsids. Biochemical and EM analyses revealed that TRIM5 proteins assembled into hexagonal nets, both alone and on capsid surfaces. These nets comprised open hexameric rings, with the SPRY domains centered on the edges and the B-box and RING domains at the vertices. Thus, the principles of hexagonal TRIM5 assembly and capsid pattern recognition are conserved across primates, allowing TRIM5 assemblies to maintain the conformational plasticity necessary to recognize divergent and pleomorphic retroviral capsids.

scholarly journals A general model for retroviral capsid pattern recognition by TRIM5 proteins

2017 ◽  
pp. JVI.01563-17 ◽  
Author(s):  
Jonathan M. Wagner ◽  
Devin E. Christensen ◽  
Akash Bhattacharya ◽  
Daria M. Dawidziak ◽  
Marcin D. Roganowicz ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Sequence Similarity ◽  
Hexagonal Lattice ◽  
Cyclophilin A ◽  
Higher Order ◽  
Restriction Factors ◽  
Defense Proteins ◽  
Spry Domain ◽  
Capsid Shell ◽  
Hiv 1

Restriction factors are intrinsic cellular defense proteins that have evolved to block microbial infections. Retroviruses such as HIV-1 are restricted by TRIM5 proteins, which recognize the viral capsid shell that surrounds, organizes, and protects the viral genome. TRIM5α uses a SPRY domain to bind capsids with low intrinsic affinity (KD>1 mM), and therefore requires higher-order assembly into a hexagonal lattice to generate sufficient avidity for productive capsid recognition. TRIMCyp, on the other hand, binds HIV-1 capsids through a cyclophilin A domain, which has a well-defined binding site and higher (KD∼10 μM) affinity for isolated capsid subunits. It has therefore been argued that TRIMCyp proteins may have dispensed with the need for higher-order assembly to function as antiviral factors. Here, we show that, consistent with its high degree of sequence similarity with TRIM5α, the TRIMCyp B-box 2 domain shares the same ability to self-associate and facilitate assembly of a TRIMCyp hexagonal lattice that can wrap about the HIV-1 capsid. We also show that under stringent experimental conditions, TRIMCyp-mediated restriction of HIV-1 is indeed dependent on higher-order assembly. Both forms of TRIM5 therefore use the same mechanism of avidity-driven capsid pattern recognition.IMPORTANCERhesus macaques and owl monkeys are highly resistant to HIV-1 infection due to the activity of TRIM5 restriction factors. The rhesus macaque TRIM5α protein blocks HIV-1 through a mechanism that requires self-assembly of a hexagonal TRIM5α lattice around the invading viral core. Lattice assembly amplifies very weak interactions between the TRIM5α SPRY domain and the HIV-1 capsid. Assembly also promotes dimerization of the TRIM5α RING E3 ligase domain, resulting in synthesis of polyubiquitin chains that mediate downstream steps of restriction. In contrast to rhesus TRIM5α, the owl monkey TRIM5 homolog, TRIMCyp, binds isolated HIV-1 CA subunits more tightly through its cyclophilin A domain, and was therefore thought to act independent of higher-order assembly. Here, we show that TRIMCyp shares the assembly properties of TRIM5α and that both forms of TRIM5 use the same mechanism of hexagonal lattice formation to promote viral recognition and restriction.

scholarly journals MxB sensitivity of HIV-1 is determined by a highly variable and dynamic capsid surface

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Richard J Miles ◽  
Claire Kerridge ◽  
Laura Hilditch ◽  
Christopher Monit ◽  
David A Jacques ◽  
...  
Keyword(s):  
Nuclear Import ◽  
Cytotoxic T Lymphocyte ◽  
Cyclophilin A ◽  
Conformational Flexibility ◽  
Restriction Factors ◽  
Nuclear Entry ◽  
Linear Forms ◽  
Cofactor Binding ◽  
Cofactor Recruitment ◽  
Hiv 1

The type one interferon induced restriction factor Myxovirus resistance B (MxB) restricts HIV-1 nuclear entry evidenced by inhibition of 2-LTR but not linear forms of viral DNA. The HIV-1 capsid is the key determinant of MxB sensitivity and cofactor binding defective HIV-1 capsid mutants P90A (defective for cyclophilin A and Nup358 recruitment) and N74D (defective for CPSF6 recruitment) have reduced dependency on nuclear transport associated cofactors, altered integration targeting preferences and are not restricted by MxB expression. This has suggested that nuclear import mechanism may determine MxB sensitivity. Here we have use genetics to separate HIV-1 nuclear import cofactor dependence from MxB sensitivity. We provide evidence that MxB sensitivity depends on HIV-1 capsid conformation, rather than cofactor recruitment. We show that depleting CPSF6 to change nuclear import pathway does not impact MxB sensitivity, but mutants that recapitulate the effect of Cyclophilin A binding on capsid conformation and dynamics strongly impact MxB sensitivity. We demonstrate that HIV-1 primary isolates have different MxB sensitivities due to cytotoxic T lymphocyte (CTL) selected differences in Gag sequence but similar cofactor dependencies. Overall our work demonstrates a complex relationship between cyclophilin dependence and MxB sensitivity likely driven by CTL escape. We propose that cyclophilin binding provides conformational flexibility to HIV-1 capsid facilitating simultaneous evasion of capsid-targeting restriction factors including TRIM5 as well as MxB.

scholarly journals Binding and Susceptibility to Postentry Restriction Factors in Monkey Cells Are Specified by Distinct Regions of the Human Immunodeficiency Virus Type 1 Capsid

2004 ◽  
Vol 78 (10) ◽  
pp. 5423-5437 ◽  
Author(s):  
Christopher M. Owens ◽  
Byeongwoon Song ◽  
Michel J. Perron ◽  
Peter C. Yang ◽  
Matthew Stremlau ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cyclophilin A ◽  
New World Monkeys ◽  
Restriction Factors ◽  
Factor Binding ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT In cells of Old World and some New World monkeys, dominant factors restrict human immunodeficiency virus type 1 (HIV-1) infections after virus entry. The simian immunodeficiency virus SIVmac is less susceptible to these restrictions, a property that is determined largely by the viral capsid protein. For this study, we altered exposed amino acid residues on the surface of the HIV-1 capsid, changing them to the corresponding residues found on the SIVmac capsid. We identified two distinct pathways of escape from early, postentry restriction in monkey cells. One set of mutants that were altered near the base of the cyclophilin A-binding loop of the N-terminal capsid domain or in the interdomain linker exhibited a decreased ability to bind the restricting factor(s). Consistent with the location of this putative factor-binding site, cyclophilin A and the restricting factor(s) cooperated to achieve the postentry block. A second set of mutants that were altered in the ridge formed by helices 3 and 6 of the N-terminal capsid domain efficiently bound the restricting factor(s) but were resistant to the consequences of factor binding. These results imply that binding of the simian restricting factor(s) is not sufficient to mediate the postentry block to HIV-1 and that SIVmac capsids escape the block by decreases in both factor binding and susceptibility to the effects of the factor(s).

Cyclophilin A modulates the sensitivity of HIV-1 to host restriction factors

10.1038/nm910 ◽  
2003 ◽  
Vol 9 (9) ◽  
pp. 1138-1143 ◽  
Author(s):  
Greg J Towers ◽  
Theodora Hatziioannou ◽  
Simone Cowan ◽  
Stephen P Goff ◽  
Jeremy Luban ◽  
...  
Keyword(s):  
Cyclophilin A ◽  
Restriction Factors ◽  
Host Restriction ◽  
Host Restriction Factors ◽  
Hiv 1

scholarly journals The Host-Pathogen interaction of human cyclophilin A and HIV-1 Vpr requires specific N-terminal and novel C-terminal domains

2011 ◽  
Vol 11 (1) ◽  
pp. 49 ◽  
Author(s):  
Sara MØ Solbak ◽  
Victor Wray ◽  
Ole Horvli ◽  
Arnt J Raae ◽  
Marte I Flydal ◽  
...  
Keyword(s):  
Cyclophilin A ◽  
Host Pathogen Interaction ◽  
Host Pathogen ◽  
Hiv 1 ◽  
Terminal Domains

Retroviral Infections of the Nervous System

2021 ◽  
pp. 1009-1015
Author(s):  
Michel Toledano ◽  
Allen J. Aksamit Jr
Keyword(s):  
Nervous System ◽  
Reverse Transcription ◽  
Rna Viruses ◽  
Neurologic Manifestations ◽  
T Lymphotropic Virus ◽  
System P ◽  
Aids Pandemic ◽  
The Family ◽  
Retroviral Infections ◽  
Hiv 1

Retroviruses are a family of RNA viruses that replicate by reverse transcription. The family includes HIV and human T-lymphotropic virus. This chapter reviews neurologic manifestations of these retroviruses. A retrovirus in the genus Lentivirus, HIV has 2 forms, HIV-1 and HIV-2. HIV-1 is associated with the global AIDS pandemic, whereas HIV-2 causes an AIDS-like illness primarily in West Africa, although pockets of infection exist globally.

scholarly journals Evolution of Cyclophilin A and TRIMCyp Retrotransposition in New World Primates

2005 ◽  
Vol 79 (23) ◽  
pp. 14998-15003 ◽  
Author(s):  
Ieda P. Ribeiro ◽  
Albert N. Menezes ◽  
Miguel A. M. Moreira ◽  
Cibele R. Bonvicino ◽  
Héctor N. Seuánez ◽  
...  
Keyword(s):  
New World ◽  
Cyclophilin A ◽  
Primate Species ◽  
Virus Infectivity ◽  
Restriction Factors ◽  
New World Primates ◽  
Immunodeficiency Virus ◽  
Host Cell Factors ◽  
Retroviral Infections

ABSTRACT Host cell factors modulate retroviral infections. Among those, cyclophilin A (CypA) promotes virus infectivity by facilitating virus uncoating or capsid unfolding or by preventing retroviral capsid interaction with cellular restriction factors. In Aotus species, a retrotransposed copy of CypA inserted into the tripartite motif 5 (TRIM5) gene encodes a fusion protein which may block human immunodeficiency virus type 1 by targeting the incoming virus to ubiquitin-ligated degradation or by interfering with normal uncoating of the incoming particle, rendering those monkeys resistant to infection. In this study, we have extensively analyzed representative specimens from all New World primate genera and shown that the retrotransposed CypA copy is only present in Aotus. We have shown that this inserted copy diverged from its original counterpart and that this occurred prior to Aotus radiation, although no positive selection was observed. Finally, our data underscores the need for a precise taxonomic identification of primate species used as models for retroviral infections and novel antiviral approaches.

scholarly journals Cyclophilin A Prevents HIV-1 Restriction in Lymphocytes by Blocking Human TRIM5α Binding to the viral Core

2019 ◽  
Author(s):  
Anastasia Selyutina ◽  
Mirjana Persaud ◽  
Angel Bulnes-Ramos ◽  
Cindy Buffone ◽  
Alicia Martinez-Lopez ◽  
...  
Keyword(s):  
T Cells ◽  
Reverse Transcription ◽  
Human Lymphocytes ◽  
Cyclophilin A ◽  
Inhibitory Effect ◽  
Jurkat Cells ◽  
Human Pbmcs ◽  
The Core ◽  
Hiv 1 ◽  
Cypa Binding

ABSTRACTDisruption of cyclophilin A (CypA)-capsid interactions affects HIV-1 replication in human lymphocytes. To understand the mechanism, we used Jurkat cells, human PBMCs, and human CD4+T cells. Our results showed that the inhibition of HIV-1 infection caused by disrupting CypA-capsid interactions is dependent on human TRIM5α (TRIM5αhu), suggesting that TRIM5αhurestricts HIV-1. Accordingly, we found that TRIM5αhubinds to the HIV-1 core. Disruption of CypA-capsid interactions failed to affect HIV-1-A92E infection, correlating with the loss of TRIM5αhubinding to HIV-1-A92E cores. Disruption of CypA-capsid interactions in PBMCs and CD4+T cells had a greater inhibitory effect on HIV-1 when compared to Jurkat cells. HIV-1-A92E infection of PBMCs and CD4+T cells was unaffected by disruption of CypA-capsid interactions. Consistent with TRIM5α restriction, disruption of CypA-capsid interactions in CD4+T cells inhibited reverse transcription. Overall, our results showed that CypA binding to the core protects HIV-1 from TRIM5αhurestriction.

scholarly journals HIV-1 evasion of restriction factors: cyclophilin A and cell fusion provide a helping hand

2018 ◽  
Author(s):  
Henry Owen ◽  
Alun Vaughan-Jackson ◽  
Lea Nussbaum ◽  
Jane Vowles ◽  
William James ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Fusion ◽  
Cyclophilin A ◽  
Host Protein ◽  
Viral Escape ◽  
Viral Reservoir ◽  
Restriction Factor ◽  
Restriction Factors ◽  
Hiv 1 ◽  
Cell Cell

AbstractRetroviral restriction factors are important regulators of viral infection, targeting vulnerable steps of the virus lifecycle; steps that are also targeted by antiviral drugs. It has become clear that the route of cellular infection can alter the sensitivity of HIV-1 to these agents. Using CRISPR-Cas9 edited pluripotent stem cell-derived macrophages, we have explored the potential of a modified restriction factor (human TRIMCyp) to inhibit HIV-1 replication in both cell free and cell-cell infection models. We show that the expression of TRIMCyp from the endogenous TRIM5α locus potently restricts infection by cell-free HIV-1. Our results also show the importance of the human cyclophilin A-HIV-1 capsid interaction for viral escape from restriction by native human TRIM5α, highlighting the evolutionary interplay between virus and this host restriction factor. However, when co-cultured with infected T cells, stem cell-derived macrophages are primarily infected by fusion between the cells. We have termed infected cells that result from these fusions heterocytia, and show that their formation overcomes multiple restriction factors and the reverse transcriptase inhibitor AZT.ImportanceAs sentinels of the immune system, macrophages are relatively resistant to infection by pathogens such as HIV-1. However, infected macrophages are found in infected patients and they play key roles in the pathogenesis of the disease as well as being a component of the viral reservoir that must be targeted before treatment can become cure. In this article, we show that some of the mechanisms by which macrophages restrict HIV-1 can be overcome through a recently described cell-cell interaction leading to cell-cell fusion. We also highlight an evolutionary battle between virus and host and show how the virus has co-opted a host protein to protect it from destruction by an antiviral mechanism. These two key findings suggest potential novel treatment strategies that may reduce the viral reservoir and help our natural defences take back control from the virus.

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