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)

The activation-induced deaminase/apolipoprotein B-editing catalytic subunit 1 (AID/APOBEC) family comprises four groups of proteins. Both AID, a lymphoid-specific DNA deaminase that triggers antibody diversification, and APOBEC2 (function unknown) are found in all vertebrates examined. In contrast, APOBEC1, an RNA-editing enzyme in gastrointestinal cells, and APOBEC3 are restricted to mammals. The function of most APOBEC3s, of which there are seven in human but one in mouse, is unknown, although several human APOBEC3s act as host restriction factors that deaminate human immunodeficiency virus type 1 replication intermediates. A more primitive function of APOBEC3s in protecting against the transposition of endogenous retroelements has, however, been proposed. Here, we focus on mouse APOBEC2 (a muscle-specific protein for which we find no evidence of a deaminating activity on cytidine whether as a free nucleotide or in DNA) and mouse APOBEC3 (a DNA deaminase which we find widely expressed but most abundant in lymphoid tissue). Gene-targeting experiments reveal that both APOBEC2 (despite being an ancestral member of the family with no obvious redundancy in muscle) and APOBEC3 (despite its proposed role in restricting endogenous retrotransposition) are inessential for mouse development, survival, or fertility.
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PMID:Mice deficient in APOBEC2 and APOBEC3. 1605 35

Enzymes that deaminate cytidine to uridine play an important role in a variety of pathways from bacteria to man. Ancestral members of this family were able to deaminate cytidine only in a mononucleotide or nucleoside context. Recently, a family of enzymes has been discovered with the ability to deaminate cytidines on RNA or DNA. The first member of this new family is APOBEC1, which deaminates apolipoprotein B messenger RNA to generate a premature stop codon. APOBEC1 has the conserved active site motif found in Escherichia coli cytidine deaminase. In addition, APOBEC1 has a unique motif containing 2 phenylalanine residues and an insert of 4 amino acid residues across the active site motif. This motif is present in APOBEC family members including activation-induced cytidine deaminase (AID), APOBEC2, and APOBEC3A through APOBEC3G. AID is essential for initiating class-switch recombination, somatic hypermutation, and gene conversion. The APOBEC3 family is unique to primates. APOBEC3G is able to protect cells from human immunodeficiency virus and other viral infections. This function is not unique to APOBEC3G; other APOBEC3 family members also have this ability. Overexpression of enzymes in this family can cause cancer, suggesting that the genes for the APOBEC family of proteins are proto-oncogenes. Recent advances in the understanding of the mechanism of action of this family are summarized in this review.
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PMID:An overview of cytidine deaminases. 1672 May 47

The interferon (IFN) system, including various IFNs and IFN-inducible gene products, is well known for its potent innate immunity against wide-range viruses. Recently, a family of cytidine deaminases, functioning as another innate immunity against retroviral infection, has been identified. However, its regulation remains largely unknown. In this report, we demonstrate that through a regular IFN-alpha/beta signal transduction pathway, IFN-alpha can significantly enhance the expression of apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G) in human primary resting but not activated CD4 T cells and the amounts of APOBEC3G associated with a low molecular mass. Interestingly, short-time treatments of newly infected resting CD4 T cells with IFN-alpha will significantly inactivate human immunodeficiency virus type 1 (HIV-1) at its early stage. This inhibition can be counteracted by APOBEC3G-specific short interfering RNA, indicating that IFN-alpha-induced APOBEC3G plays a key role in mediating this anti-HIV-1 process. Our data suggest that APOBEC3G is also a member of the IFN system, at least in resting CD4 T cells. Given that the IFN-alpha/APOBEC3G pathway has potent anti-HIV-1 capability in resting CD4 T cells, augmentation of this innate immunity barrier could prevent residual HIV-1 replication in its native reservoir in the post-highly active antiretroviral therapy era.
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PMID:Alpha interferon potently enhances the anti-human immunodeficiency virus type 1 activity of APOBEC3G in resting primary CD4 T cells. 1684 Mar 43

Deoxycytidine deaminases APOBEC3G (A3G) and APOBEC3F (A3F) (members of the apolipoprotein B mRNA-editing catalytic polypeptide 3 family) have RNA-binding motifs, invade assembling human immunodeficiency virus (HIV-1), and hypermutate reverse transcripts. Antagonistically, HIV-1 viral infectivity factor degrades these enzymes. A3G is enzymatically inhibited by binding RNA within an unidentified large cytosolic ribonucleoprotein, implying that RNA degradation during reverse transcription may activate intravirion A3G at the necessary moment. We purified a biologically active tandem affinity-tagged A3G from human HEK293T cells. Mass spectrometry and coimmunoprecipitation from HEK293T and T lymphocyte extracts identified many RNA-binding proteins specifically associated with A3G and A3F, including poly(A)-binding proteins (PABPs), YB-1, Ro-La, RNA helicases, ribosomal proteins, and Staufen1. Most strikingly, nearly all A3G-associated proteins were known to bind exclusively or intermittently to translating and/or dormant mRNAs. Accordingly, A3G in HEK293T and T lymphocyte extracts was almost completely in A3G-mRNA-PABP complexes that shifted reversibly between polysomes and dormant pools in response to translational inhibitors. For example arsenite, which inhibits 5'-cap-dependent translational initiation, shifted mRNA-A3G-PABP from polysomes into stress granules in a manner that was blocked and reversed by the elongation inhibitor cycloheximide. Immunofluorescence microscopy showed A3G-mRNA-PABP stress granules only partially overlapping with Staufen1. A3G coimmunoprecipitated HIV-1 RNA and many mRNAs. Ribonuclease released nearly all A3G-associated proteins, including A3G homo-oligomers and A3G-A3F hetero-oligomers, but the viral infectivity factor remained bound. Many proteins and RNAs associated with A3G are excluded from A3G-containing virions, implying that A3G competitively partitions into virions based on affinity for HIV-1 RNA.
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PMID:The anti-HIV-1 editing enzyme APOBEC3G binds HIV-1 RNA and messenger RNAs that shuttle between polysomes and stress granules. 1688 8

Old World monkey TRIM5alpha targets incoming human immunodeficiency virus type 1 (HIV-1) viral capsid, whereas the apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like (APOBEC)3 family hypermutate/degrade viral sequences. Here, we show the potentials of simian TRIM5alpha and APOBEC3G as therapeutic sequences for AIDS gene therapy. Both rhesus and African green monkey (agm) TRIM5alpha efficiently restrict HIV-1 vectors with divergent Gag from different HIV-1 subtypes. Human T cells genetically engineered to express agm-TRIM5alpha block or delay HIV-1 replication. Although agm-APOBEC3G expression alone only transiently suppresses HIV-1 replication, co-expression of agm-APOBEC3G and agm-TRIM5alpha successfully block the virus replication for more than 5 weeks.
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PMID:Inhibition of HIV-1 replication by simian restriction factors, TRIM5alpha and APOBEC3G. 1694 52

APOBEC3G (an apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G; also known as CEM15), a member of the APOBEC family, which possesses cytidine deaminase activity that causes C/G to T/A transition mutations in virus genomes such as human immunodeficiency virus 1 and hepatitis B virus, is reported to play an important role in host-defense mechanisms. However, APOBEC3G expression in patients infected with chronic hepatitis C virus (HCV), of which there are currently more than 170 million worldwide, has not yet been well studied. We investigated this issue herein, and demonstrated an increased expression of APOBEC3G in both hepatocytes and lymphocytes of chronic hepatitis patients infected with HCV. Transfection of the NS5A gene, but not any other non-structural protein genes of HCV tested, to the hepatocellular carcinoma cell line enhanced APOBEC3G expression. Incubation of the cells with interferon also resulted in the augmentation. These results may provide new insight into the pathogenesis of chronic HCV infection.
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PMID:High expression of APOBEC3G in patients infected with hepatitis C virus. 1703 63

The introduction of highly active antiretroviral therapy (HAART) combining potent drugs that can inhibit reverse transcriptase, integrase and protease activities has changed the natural history of the human immunodeficiency virus (HIV) type 1 disease. Unfortunately, poor penetrability into different anatomic compartments, toxicity and drug resistance are some of the problems related to their prolonged use. The ability of HIV to mutate and become resistant, along with the ongoing viral replication during HAART, can lead to the emergence of independently evolving viral strains in different anatomic compartments (i.e., brain, testes, lymph nodes, etc.). In addition, HAART predominantly effects the viral replication in the activated or differentiating CD(+) T lymphocytes, but appears to have a very limited effect on HIV-1 preintegration complexes in the latently infected cells. Existing drug therapies do not eliminate these viral reservoirs, nor do they prevent their formation. New strategies are needed for eliminating protected areas of HIV-1 in vivo. Therefore, the persistence of latent HIV-1 reservoirs is the principal barrier in the complete eradication of HIV-1 infection in patients by antiretroviral therapy at present. African non-human primates (NHPs) naturally infected with various simian immunodeficiency viruses (SIVs) appear not to develop immunodeficiency or AIDS, whereas Asian NHPs, which are unnatural hosts, infected with SIVs, as well humans infected with HIV-1, will nearly always develop progressive loss of CD(+) T lymphocytes and a gradual destruction of immune functions. Understanding the difference in the host responses between natural and unnatural hosts, and deciphering which host factors are responsible for the non-pathogenic course of natural SIV infections, would be valuable in developing more-effective treatment or prevention strategies for HIV/AIDS. A number of factors encoded by host cells have been identified that appear to play critical roles in the SIV infection process. Two of these factors, TRIM5alpha (a member of a large family of proteins known as the TRIM proteins) and cellular apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like-3G (APOBEC3G) have been recently identified. APOBEC3G genes belong to a family of primate genes that produce enzymes (in this case, APOBEC3G) that 'edit' RNA by replacing cytosine with guanine into viral particles as the virus undergoes reverse transcription in the cytoplasm of the host cell. HIV-1, in turn, counters with a protein called viral infectivity factor (Vif), which binds to the APOBEC3G enzyme that degrades it. Several other blocking factors have been described, including lentiviral blocking factor (Lv)1 and 2. These factors appear to block the infection at a postentry step; after reverse transcription has occurred, but before proviral integration. Thus, it is crucial to understand the molecular mechanisms involved in the establishment, maintenance and reactivation of lentiviral latency. This review presents various models of HIV-1 latency and forward a new unified model of lentiviral latency.
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PMID:A unified concept of HIV latency. 1704 12

The narrow host range of human immunodeficiency virus type 1 (HIV-1) is caused in part by innate cellular factors such as apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G) and TRIM5alpha, which restrict virus replication in monkey cells. Variant HIV-1 molecular clones containing both a 21-nucleotide simian immunodeficiency virus (SIV) Gag CA element, corresponding to the HIV-1 cyclophilin A-binding site, and the entire SIV vif gene were constructed. Long-term passage in a cynomolgus monkey lymphoid cell line resulted in the acquisition of two nonsynonymous changes in env, which conferred improved replication properties. A proviral molecular clone, derived from infected cells and designated NL-DT5R, was used to generate virus stocks capable of establishing spreading infections in the cynomolgus monkey T cell line and CD8-depleted peripheral blood mononuclear cells from five of five pig-tailed macaques and one of three rhesus monkeys. NL-DT5R, which genetically is >93% HIV-1, provides the opportunity, not possible with currently available SIV/HIV chimeric viruses, to analyze the function of multiple HIV-1 genes in a broad range of nonhuman primate species.
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PMID:Generation of HIV-1 derivatives that productively infect macaque monkey lymphoid cells. 1706 15

APOBEC-2 (APO2) belongs to the family of apolipoprotein B messenger RNA-editing enzyme catalytic (APOBEC) polypeptides, which deaminates mRNA and single-stranded DNA. Different APOBEC members use the same deamination activity to achieve diverse human biological functions. Deamination by an APOBEC protein called activation-induced cytidine deaminase (AID) is critical for generating high-affinity antibodies, and deamination by APOBEC-3 proteins can inhibit retrotransposons and the replication of retroviruses such as human immunodeficiency virus and hepatitis B virus. Here we report the crystal structure of APO2. APO2 forms a rod-shaped tetramer that differs markedly from the square-shaped tetramer of the free nucleotide cytidine deaminase, with which APOBEC proteins share considerable sequence homology. In APO2, two long alpha-helices of a monomer structure prevent the formation of a square-shaped tetramer and facilitate formation of the rod-shaped tetramer via head-to-head interactions of two APO2 dimers. Extensive sequence homology among APOBEC family members allows us to test APO2 structure-based predictions using AID. We show that AID deamination activity is impaired by mutations predicted to interfere with oligomerization and substrate access. The structure suggests how mutations in patients with hyper-IgM-2 syndrome inactivate AID, resulting in defective antibody maturation.
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PMID:The APOBEC-2 crystal structure and functional implications for the deaminase AID. 1718 54

The apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G), a member of the APOBEC family possessing DNA mutator activity through cytosine deamination, is reported to play an important role in host defense against infections such as those of hepatitis B virus and human immunodeficiency virus. Here, we examined the expression of APOBEC3G in human kidney cells to better understand its biological role against infection. APOBEC3G was immunohistochemically detectable in kidney mesangial cells and also to some extent in kidney epithelial tubular cells. In addition, overexpression of APOBEC3G was shown in renal carcinoma tissues and cell lines. APOBEC3G expression was upregulated by inflammatory cytokines, such as interferon, interleukin-6, and tumor necrosis factor. These results may provide new insight into the role of APOBEC3G in host defense against viral infection and cancer.
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PMID:Expression of APOBEC3G in kidney cells. 1721 12


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