Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The virion infectivity factor (Vif) accessory protein of HIV-1 forms a complex with the cellular cytidine deaminase APOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G) to block its antiviral activity. The antiviral property of APOBEC3G is conserved in several mammalian species, but the ability of Vif to block this activity is species-specific. HIV-1 Vif blocks human APOBEC3G but does not block the mouse or African green monkey (AGM) enzyme. Conversely, SIV(AGM) Vif blocks the antiviral activity of AGM but not human APOBEC3G. We demonstrate that the species specificity is caused by a single amino acid difference in APOBEC3G. Replacement of Asp-128 in human APOBEC3G with the Lys-128 of AGM APOBEC3G caused the enzyme to switch its interaction, becoming sensitive to SIV(AGM) Vif and resistant to HIV-1 Vif. Conversely, the reciprocal Lys to Asp switch in AGM APOBEC3G reversed its specificity for Vif. The reversal of biological activity was accompanied by the corresponding switch in the species specificity with which the enzyme physically associated with Vif and was excluded from virions. The charge of the amino acid at position 128 was a critical determinant of species specificity. Based on the crystal structure of the distantly related Escherichia coli cytidine deaminase, we propose that this amino acid is positioned on a solvent-exposed loop of APOBEC3G on the same face of the protein as the catalytic site.
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PMID:A single amino acid of APOBEC3G controls its species-specific interaction with virion infectivity factor (Vif). 1501 May 28

The HIV type 1 (HIV-1) virion infectivity factor (Vif) protein blocks the action of the host defense factor APOBEC3G in human cells, thereby allowing release of infectious virions, but fails to inhibit similar APOBEC3G proteins present in some simian cells. Conversely, the Vif protein encoded by the African green monkey (agm) simian immunodeficiency virus (SIV) can block agm APOBEC3G function but fails to inhibit human APOBEC3G. This difference plays a key role in determining the primate species tropism of HIV-1 and SIV agm. Here, we demonstrate that a single APOBEC3G residue, which is an aspartic acid in human APOBEC3G and a lysine in agm APOBEC3G, controls the ability of the HIV-1 Vif protein to bind and inactivate these host defense factors. These data identify a critical charged residue that plays a key role in mediating the formation of the distinct Vif:APOBEC3G complexes formed in human and simian cells. Moreover, these results suggest that the biological barrier preventing the entry of additional SIV into the human population as zoonotic infections is potentially quite fragile.
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PMID:A single amino acid difference in the host APOBEC3G protein controls the primate species specificity of HIV type 1 virion infectivity factor. 1501 May 28

The viral infectivity factor (Vif), one of the six HIV-1 auxiliary genes, is absolutely necessary for productive infection in primary CD4-positive T lymphocytes and macrophages. Vif overcomes the antiviral function of the host factor APOBEC3G. To better understand this mechanism, it is of interest to characterize cellular proteins that interact with Vif and may regulate its function. Here, we show that Vif binds to hNedd4 and AIP4, two HECT E3 ubiquitin ligases. WW domains present in those HECT enzymes contribute to the binding of Vif. Moreover, the region of Vif, which includes amino acids 20-128 and interacts with the hNedd4 WW domains, does not contain proline-rich stretches. Lastly, we show that Vif undergoes post-translational modifications by addition of ubiquitin both in cells overexpressing Vif and in cells expressing HIV-1 provirus. Vif is mainly mono-ubiquitinated, a modification known to address the Gag precursor to the virus budding site.
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PMID:The Vif protein of human immunodeficiency virus type 1 is posttranslationally modified by ubiquitin. 1501 26

To investigate the extent to which in vivo mutation spectra might reflect the intrinsic specificities of active mutators, genetic and biochemical assays were used to analyse the DNA target specificities of cytidine deaminases of the APOBEC family. The results reveal the critical importance of nucleotides immediately 5' of the targeted C for the specificity of all three enzymes studied (AID, APOBEC1 and APOBEC3G). At position -1, APOBEC1 showed a marked preference for dT, AID for dA/dG and APOBEC3G a strong preference for dC. Furthermore, AID and APOBEC3G showed distinct dependence on the nucleotide at position -2 with dA/dT being favoured by AID and dC by APOBEC3G. Most if not all activity of the recombinant deaminases on free dC could be attributed to low-level contamination by host enzymes. The target preference of APOBEC3G supports it being a major but possibly not sole contributor to HIV hypermutation without making it a dominant contribution to general HIV sequence variation. The specificity of AID as deduced from the genetic assay (which relies on inactivation of sacB of Bacillus subtilis) agrees well with that deduced by Pham et al. using an in vitro assay although we postulate that major intrinsic mutational hotspots in immunoglobulin V genes in vivo might reflect favoured sites of AID action being generated by proximal DNA targets located on opposite DNA strands. The target specificity of AID also accords with the spectrum of mutations observed in B lymphoma-associated oncogenes. The possibility of deaminase involvement in non-lymphoid human tumours is hinted at by tissue-specific differences in the spectra of dC transitions in tumour-suppressor genes. Thus, the patterns of hypermutation in antibodies and retroviruses owe much to the intrinsic sequence preferences of the AID/APOBEC family of DNA deaminases: analogous biases might also contribute to the spectra of cancer-associated mutation.
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PMID:Comparison of the differential context-dependence of DNA deamination by APOBEC enzymes: correlation with mutation spectra in vivo. 1501 79

HIV-1 deleted for the vif accessory gene encapsidates the cellular cytidine deaminase APOBEC3G. Upon infection, the encapsidated APOBEC3G induces G-->A mutations in the viral reverse transcripts. The G-->A mutations result either from C-->U deamination of the minus strand or deamination of both strands followed by repair of the plus strand. We report here that minus-strand deamination occurred over the length of the virus genome, preferentially at CCCA sequences, with a graded frequency in the 5'-->3' direction. APOBEC3G induced previously undetected C-->T mutations in the 5' U3 and the primer-binding site, both of which become transiently single-stranded during reverse transcription. In vitro, APOBEC3G bound and deaminated single-stranded DNA (ssDNA) but not double-stranded DNA (dsDNA) or DNA-RNA hybrids. We propose that the requirement for ssDNA accounts for the minus-strand mutations, the 5'-->3' graded frequency of deamination and the rare C-->T mutations.
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PMID:Single-strand specificity of APOBEC3G accounts for minus-strand deamination of the HIV genome. 1509 18

Recently, APOBEC3G has been identified as a host factor that blocks retroviral replication. It introduces G to A hypermutations in newly synthesized minus strand viral cDNA at the step of reverse transcription in target cells. Here, we identified the human APOBEC3F protein as another host factor that blocks human immunodeficiency virus type 1 (HIV-1) replication. Similar to APOBEC3G, APOBEC3F also induced G to A hypermutations in HIV genomic DNA, and the viral Vif protein counteracted its activity. Thus, APOBEC family members might have evolved as a general defense mechanism of the body against retroviruses, retrotransposons, and other mobile genetic elements.
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PMID:Human APOBEC3F is another host factor that blocks human immunodeficiency virus type 1 replication. 1514 Oct 7

The HIV-1 Vif protein suppresses the inhibition of viral replication caused by the human antiretroviral factor APOBEC3G. As a result, HIV-1 mutants that do not express the Vif protein are replication incompetent in 'nonpermissive' cells, such as primary T cells and the T-cell line CEM, that express APOBEC3G. In contrast, Vif-defective HIV-1 replicates effectively in 'permissive' cell lines, such as a derivative of CEM termed CEM-SS, that do not express APOBEC3G. Here, we show that a second human protein, APOBEC3F, is also specifically packaged into HIV-1 virions and inhibits their infectivity. APOBEC3F binds the HIV-1 Vif protein specifically and Vif suppresses both the inhibition of virus infectivity caused by APOBEC3F and virion incorporation of APOBEC3F. Surprisingly, APOBEC3F and APOBEC3G are extensively coexpressed in nonpermissive human cells, including primary lymphocytes and the cell line CEM, where they form heterodimers. In contrast, both genes are quiescent in the permissive CEM derivative CEM-SS. Together, these data argue that HIV-1 Vif has evolved to suppress at least two distinct but related human antiretroviral DNA-editing enzymes.
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PMID:A second human antiretroviral factor, APOBEC3F, is suppressed by the HIV-1 and HIV-2 Vif proteins. 1515 92

The viral protein, Vif, is essential for the production of infectious progeny virions in natural target cells of human immunodeficiency virus type 1 (HIV-1). Several recent reports indicate that Vif acts by antagonizing the activity of an endogenous human antiviral protein, APOBEC3G. To investigate this route to restrict HIV-1 infection, we employed mutagenesis to assess APOBEC3G function during HIV-1 infection including interaction with Vif, localization, and activity in virions. We found that APOBEC3G binds Vif in infected cells and the C'-terminal region is required for this interaction. APOBEC3G was only incorporated into virions in the absence of Vif and deletion of either the N'-terminal or C'-terminal regions of APOBEC3G abrogated virion localization. Assaying endogenous reverse transcription we found that APOBEC3G and its C'-terminal deletion mutant inhibited full-length cDNA synthesis, possibly through binding to viral RNA, a function revealed through gel-shift assays. Taken together, our studies suggest that APOBEC3G inhibits HIV-1 infection through interference with reverse transcription and that Vif counteracts APOBEC3G by impeding its entry into virions.
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PMID:Functional domains of APOBEC3G required for antiviral activity. 1515 67

APOBEC3G, a member of an RNA/DNA cytidine deaminase superfamily, has been identified as a cellular inhibitor of HIV-1 infectivity, possibly through the dC to dU deamination of the first minus strand cDNA synthesized during reverse transcription. Virions incorporate APOBEC3G during viral assembly in non-permissive cells, and this incorporation is inhibited by the viral protein Vif. The mechanism of APOBEC3G incorporation into HIV-1 is examined in this report. In the absence of Vif, cytoplasmic APOBEC3G becomes membrane-bound in cells expressing HIV-1 Gag, and its incorporation into Gag viral-like particles (VLPs) is proportional to the amount of APOBEC3G expressed in the cell. The expression of Vif, or mutant Gag unable to bind to membrane, prevents the APOBEC3G association with membrane. HIV-1 Gag alone among viral proteins is sufficient for packaging of APOBEC3G into Gag VLPs, and this incorporation requires the presence of Gag nucleocapsid. The presence of amino acids 104-156 in APOBEC3G, located in the linker region between two zinc coordination motifs, is also required for its incorporation into Gag VLPs. Evidence against an RNA bridge facilitating the Gag/APOBEC3G interaction includes data indicating that 1) the incorporation of APOBEC3G occurs independently of viral genomic RNA, 2) a Gag/APOBEC3G complex is immunoprecipitated from cell lysate after RNase treatment, and 3) the zinc coordination motif, rather than the regions flanking this motif, have been implicated in RNA binding in another family member, APOBEC1.
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PMID:The interaction between HIV-1 Gag and APOBEC3G. 1515 5

HIV-1 and most of the other lentiviruses encode Vif (virion infectivity factor), an accessory protein that the virus requires to replicate in primary CD4+ T-cells and monocytes. The host cell factor with which Vif interacts was recently identified as APOBEC3G, a cytidine deaminase related to the RNA-editing enzymes. Identification of this key host protein has allowed for dramatic leaps in our understanding of how Vif functions. Vif prevents the encapsidation of APOBEC3G into HIV-1 virions during virus assembly. If not for Vif, the encapsidated APOBEC3G would damage the virus reverse transcripts, causing their degradation and closing the open reading frames of its genes.
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PMID:New insights into the role of Vif in HIV-1 replication. 1516 39


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