Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vif is a primate lentiviral accessory protein that is crucial for viral infectivity. Vif counteracts the antiviral activity of host deaminases such as APOBEC3G and APOBEC3F. We now report a novel function of African green monkey simian immunodeficiency virus (SIVagm) Vif that promotes replication of SIVagm in human cells lacking detectable deaminase activity. We found that cyclophilin A (CypA) was excluded from wild-type SIV particles but was efficiently packaged into vif-deficient SIVagm virions. The presence of CypA in vif-defective SIVagm was correlated with reduced viral replication. Infection of CypA knockout Jurkat cells or treatment of Jurkat cells with cyclosporine A eliminated the Vif-sensitive inhibition and resulted in replication profiles that were similar for wild-type and vif-deficient SIVagm. Importantly, the inhibitory effect of CypA was restricted to virus-producing cells and was TRIM5alpha independent. The abilities of SIVagm Vif to inhibit encapsidation of CypA and to increase viral infectivity were shared by rhesus macaque SIV Vif and thus seem to be general properties of SIV Vif proteins. Exclusion of CypA from SIVagm particles was not associated with intracellular degradation, suggesting a mode of Vif action distinct from that proposed for APOBEC3G. This is the first report of a novel vif-sensitive antiviral activity of human CypA that may limit zoonotic transmission of SIV and the first demonstration of CypA encapsidation into a virus other than human immunodeficiency virus type 1.
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PMID:Vif counteracts a cyclophilin A-imposed inhibition of simian immunodeficiency viruses in human cells. 1752 32

The retroviral restriction factors, TRIM5alpha and TRIMCyp, consist of RING and B-box 2 domains separated by a coiled coil from carboxy-terminal domains. These carboxy-terminal domains (the B30.2(SPRY) domain in TRIM5alpha and the cyclophilin A domain in TRIMCyp) recognize the retroviral capsid. Here we show that some B-box 2 changes in TRIM5alpha, but not in TRIMCyp, resulted in decreased human immunodeficiency virus (HIV-1) capsid binding. The phenotypic effects of these B-box 2 changes on the restriction of retroviral infection depended on the potency of restriction and the affinity of the TRIM5alpha interaction with the viral capsid, two properties specified by the B30.2(SPRY) domain. Thus, some alterations in the TRIM5alpha B-box 2 domain apparently affect the orientation or conformation of the B30.2(SPRY) domain, influencing capsid recognition.
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PMID:Functional interplay between the B-box 2 and the B30.2(SPRY) domains of TRIM5alpha. 1754 65

In owl monkeys, the typical retroviral restriction factor of primates, TRIM5alpha, is replaced by TRIMCyp. TRIMCyp consists of the TRIM5 RING, B-box 2 and coiled-coil domains, as well as the intervening linker regions, fused with cyclophilin A. TRIMCyp restricts infection of retroviruses, such as human immunodeficiency virus (HIV-1) and feline immunodeficiency virus (FIV), with capsids that can bind cyclophilin A. The TRIM5 coiled coil promotes the trimerization of TRIMCyp. Here we show that cyclophilin A that is oligomeric as a result of fusion with a heterologous multimer exhibits substantial antiretroviral activity. The addition of the TRIM5 RING, B-box 2 and Linker 2 to oligomeric cyclophilin A generated a protein with antiretroviral activity approaching that of wild-type TRIMCyp. Multimerization increased the binding of cyclophilin A to the HIV-1 capsid, promoting accelerated uncoating of the capsid and restriction of infection.
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PMID:The ability of multimerized cyclophilin A to restrict retrovirus infection. 1757 42

Primate genomes contain a large number of endogenous retroviruses and encode evolutionarily dynamic proteins that provide intrinsic immunity to retroviral infections. We report here the resurrection of the core protein of a 4-million-year-old endogenous virus from the chimpanzee genome and show that the human variant of the intrinsic immune protein TRIM5alpha can actively prevent infection by this virus. However, we suggest that selective changes that have occurred in the human lineage during the acquisition of resistance to this virus, and perhaps similar viruses, may have left our species more susceptible to infection by human immunodeficiency virus type 1 (HIV-1).
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PMID:Restriction of an extinct retrovirus by the human TRIM5alpha antiviral protein. 1758 33

In light of findings demonstrating that the macaque TRIM5alpha protein inhibits infection of cells by human immunodeficiency virus (HIV)-1, simian immunodeficiency virus (SIV)-based lentiviral vectors may have distinct advantages over HIV-1 vectors for the transduction of macaque hematopoietic stem cells. We evaluated the ability of an SIV vector (VRX859) encoding an antisense SIV envelope sequence and enhanced green fluorescent protein (GFP) to inhibit viral replication and to transduce rhesus CD34(+) lymphoid progenitor cells. After infection with homologous SIV strains, CD4(+) cell lines transduced with VRX859 exhibited more than 600-fold inhibition of viral replication compared with control cells. Less inhibition was observed with the divergent SIV strain SIVsmE660. Partial inhibition of a chimeric simian-human immunodeficiency virus, which contains an HIV-1 envelope in an SIV backbone, was observed, suggesting that the SIV vector also contributes to viral inhibition independent of the antisense envelope inhibitor. Transduction of rhesus CD34(+) cells with VRX859 at various multiplicities of infection resulted in transduction efficiencies comparable to those obtained with the HIV vector VRX494. However, when we evaluated transduction of rhesus T lymphocyte progenitors by examining GFP expression in CD4(+) T cells derived from transduced CD34(+) cells, we observed more efficient transduction with the SIV-based vector. GFP(+)CD4(+) T cells derived from VRX859-transduced CD34(+) cells strongly inhibited SIVmac239 replication as compared with control CD4(+) T cells. The ability of this SIV-based vector to mediate potent inhibition of SIV replication, coupled with its efficient transduction of rhesus hematopoietic progenitor cells, make it an important candidate for proof-of-principle experiments of stem cell gene therapy in the SIV-macaque model.
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PMID:Potent inhibition of simian immunodeficiency virus (SIV) replication by an SIV-based lentiviral vector expressing antisense Env. 1760 Apr 61

TRIM5alpha is a potent intracellular antiviral restriction factor governing species-specific retroviral replication. In the New World species owl monkey the coding region for the viral binding B30.2 domain of TRIM5alpha has been replaced by a cyclophilin A (CypA) pseudogene by retrotransposition. The resultant TRIM5-CypA fusion protein restricts human immunodeficiency virus type 1 (HIV-1), as well as feline immunodeficiency virus (FIV), by recruitment of the CypA domain to the incoming viral capsids. Infectivity is rescued by agents such as cyclosporine that disrupt CypA binding to its substrates. Mice encode an antiviral restriction factor called Fv1 (for Friend virus susceptibility gene 1), which is active against murine leukemia virus and related to endogenous gag sequences. Here we show that fusing CypA to Fv1 generates a restriction factor with the antiviral specificity of TRIMCyp but the antiviral properties of Fv1. Like TRIMCyp, Fv1-Cyp restricts HIV-1 and FIV and is sensitive to inhibition by cyclosporine. TRIM5alpha is known to have a short half-life and block infectivity before viral reverse transcription. We show that Fv1-Cyp has a long half-life and blocks after reverse transcription, suggesting that its longer half-life gives the restricted virus the opportunity to synthesize DNA, leading to a later block to infection. This notion is supported by the observation that infectivity of Fv1-Cyp restricted virus can be rescued by cyclosporine for several hours after infection, whereas virus restricted by TRIMCyp is terminally restricted after around 40 min. Intriguingly, the Fv1-Cyp-restricted HIV-1 generates closed circular viral DNA, suggesting that the restricted virus complex enters the nucleus.
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PMID:Fusion of cyclophilin A to Fv1 enables cyclosporine-sensitive restriction of human and feline immunodeficiency viruses. 1760 68

Dominant, constitutively expressed antiretroviral factors, including TRIM5alpha and APOBEC3 proteins, are distinguished from the conventional innate immune systems and are classified as intrinsic immunity factors. Here, we demonstrate that interferon alpha (IFN-alpha) treatment upregulates TRIM5alpha mRNA in rhesus monkey cells, which correlates with the enhanced TRIM5alpha-mediated pre- and postintegration blocks of human immunodeficiency virus replication. In human cells, IFN-alpha increases the levels of TRIM5alpha mRNA, resulting in enhanced antiviral activity against N-tropic murine leukemia virus infection. These observations indicate that the TRIM5alpha-mediated antiviral effects can be orchestrated by the conventional innate immune response. It is conceivable that TRIM5alpha plays an essential role in controlling both the initial retroviral exposure and the subsequent viral dissemination in vivo.
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PMID:Alpha interferon enhances TRIM5alpha-mediated antiviral activities in human and rhesus monkey cells. 1760 77

The host cell protein cyclophilin A (CypA) binds to CA of human immunodeficiency virus type 1 (HIV-1) and promotes HIV-1 infection of target cells. Disruption of the CypA-CA interaction, either by mutation of the CA residue at G89 or P90 or with the immunosuppressive drug cyclosporine (CsA), reduces HIV-1 infection. Two CA mutants, A92E and G94D, previously were identified by selection for growth of wild-type HIV-1 in cultures of CD4(+) HeLa cell cultures containing CsA. Interestingly, infection of some cell lines by these mutants is enhanced in the presence of CsA, while in other cell lines these mutants are minimally affected by the drug. Little is known about this cell-dependent phenotype of the A92E and G94D mutants, except that it is not dependent on expression of the host factor TRIM5alpha. Here, we show that infection by the A92E and G94D mutants is restricted at an early post-entry stage of the HIV-1 life cycle. Analysis of heterokaryons between CsA-dependent HeLa-P4 cells and CsA-independent 293T cells indicated that the CsA-dependent infection by A92E and G94D mutants is due to a dominant cellular restriction. We also show that addition of CsA to target cells inhibits infection by wild-type HIV-1 prior to reverse transcription. Collectively, these results support the existence of a cell-specific human cellular factor capable of restricting HIV-1 at an early post-entry step by a CypA-dependent mechanism.
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PMID:Analysis of human cell heterokaryons demonstrates that target cell restriction of cyclosporine-resistant human immunodeficiency virus type 1 mutants is genetically dominant. 1771 16

The recent identification of antiretroviral tripartite motif-bearing restriction factors that protect against retroviral infection has revealed a novel branch of innate immunity. The factors target the retroviral capsid and inhibit infectivity soon after the capsid has entered the cytoplasm by an incompletely characterized mechanism. Restriction is species specific. For example, TRIM5alpha from Old World monkeys, but not humans, restricts human immunodeficiency virus type 1 infection. Here, we identify an antiviral TRIM5 molecule in rabbits that is closely related to antiviral TRIM5 of both primates and cattle. We demonstrate that the rabbit TRIM5 protein is active against divergent retroviruses and leads to a strong block to viral DNA synthesis and infectivity. Furthermore, we show that antiviral activity is directed against the viral capsid and that human TRIM5 proteins are dominant negative to restriction in rabbit cells. We propose that the sequence and restriction characteristics conserved between restriction factors from primates, cattle, and rabbits indicate that these factors have evolved from a common ancestor with antiretroviral properties.
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PMID:An active TRIM5 protein in rabbits indicates a common antiviral ancestor for mammalian TRIM5 proteins. 1772 24

Dendritic cells are central to the early events of human immunodeficiency virus type 1 (HIV-1) transmission, but HIV-1 infects dendritic cells inefficiently in vitro compared to activated CD4(+) T cells. There is a strong postentry restriction of HIV-1 infection in dendritic cells, partly mediated by the cellular restriction factor APOBEC3G. Here, we reveal that arsenic trioxide markedly increases HIV infection of immature and mature dendritic cells as well as blood-derived myeloid dendritic cells in an APOBEC3G- and TRIM5alpha-independent way. Our data suggest the presence of powerful, arsenic-sensitive antiviral activities in primary human immune cells of the dendritic cell lineage.
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PMID:Identification of an arsenic-sensitive block to primate lentiviral infection of human dendritic cells. 1772 30


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