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 HIV-1 p51/p66 reverse transcriptase (RT) heterodimer interface comprises, in part, intermolecular interaction of the loop region between beta-strands 7 and 8 (beta7-beta8 loop) in the p51 fingers subdomain with the p66 palm subdomain. In this study, for the first time in the context of infectious HIV-1 particles, we analyzed the contribution of amino acid residues (S134, I135, N136, N137, T139 and P140) in the beta7-beta8 loop for RT heterodimerization, enzymatic activity, and virus infectivity. Mutating asparagine 136 to alanine (N136A) reduced viral infectivity and enzyme activity dramatically. The N136A mutation appeared to destabilize the RT heterodimer and render both the p66 and p51 subunits susceptible to aberrant cleavage by the viral protease. Subunit-specific mutagenesis demonstrated that the presence of the N136A mutation in the p51 subunit alone was sufficient to cause degradation of RT within the virus particle. Alanine mutation at other residues of the beta7-beta8 loop did not affect either RT stability or virus infectivity significantly. None of the beta7-beta8 loop alanine mutations affected the sensitivity of virus to inhibition by NNRTIs. In the context of infectious virions, our results indicate a critical role of the p51 N136 residue within the beta7-beta8 loop for RT heterodimer stability and function. These findings suggest the interface comprising N136 in p51 and interacting residues in p66 as a possible target for rational drug design.
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PMID:Analysis of amino acids in the beta7-beta8 loop of human immunodeficiency virus type 1 reverse transcriptase for their role in virus replication. 1714 5

The membrane-proximal external region (MPER) of human immunodeficiency virus type 1 (HIV-1) gp41 bears the epitopes of two broadly neutralizing antibodies (Abs), 2F5 and 4E10, making it a target for vaccine design. A third Ab, Fab Z13, had previously been mapped to an epitope that overlaps those of 2F5 and 4E10 but only weakly neutralizes a limited set of primary isolates. Here, libraries of Fab Z13 variants displayed on phage were engineered and affinity selected against an MPER peptide and recombinant gp41. A high-affinity variant, designated Z13e1, was isolated and found to be approximately 100-fold improved over the parental Fab not only in binding affinity for the MPER antigens but also in neutralization potency against sensitive HIV-1. Alanine scanning of MPER residues 664 to 680 revealed that N671 and D674 are crucial for peptide recognition as well as for the neutralization of HIV-1 by Z13e1. Ab competition studies and truncation of MPER peptides indicate that Z13e1 binds with high affinity to an epitope between and overlapping with those of 2F5 and 4E10, with the minimal peptide epitope WASLWNWFDITN. Still, Z13e1 remained about an order of magnitude less potent than 4E10 against several isolates of pseudotyped HIV-1. The sum of our molecular analyses with Z13e1 suggests that the segment on the MPER of gp41 between the 2F5 and 4E10 epitopes is exposed on the functional envelope trimer but that access to the specific Z13e1 epitope within this segment is limited. Thus, the ability of MPER-bearing immunogens to elicit potent HIV-1-neutralizing Abs may depend in part on recapitulating the particular constraints that the functional envelope trimer imposes on the segment of the MPER to which Z13e1 binds.
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PMID:An affinity-enhanced neutralizing antibody against the membrane-proximal external region of human immunodeficiency virus type 1 gp41 recognizes an epitope between those of 2F5 and 4E10. 1728 72

The human tripartite motif (TRIM) family comprises 70 members, including HIV restriction factor TRIM5alpha and disease-associated proteins TRIM20 (pyrin) and TRIM21. TRIM proteins have conserved domain architecture but diverse cellular roles. Here, we describe how the C-terminal PRYSPRY domain mediates diverse TRIM functions. The crystal structure of TRIM21 PRYSPRY in complex with its target IgG Fc reveals a canonical binding interface comprised of two discrete pockets formed by antibody-like variable loops. Alanine scanning of this interface has identified the hot-spot residues that control TRIM21 binding to Fc; the same hot-spots control HIV/murine leukemia virus restriction by TRIM5alpha and mediate severe familial Mediterranean fever in TRIM20/pyrin. Characterization of the IgG binding site for TRIM21 PRYSPRY reveals TRIM21 as a superantigen analogous to bacterial protein A and suggests that an antibody bipolar bridging mechanism may contribute to the pathogenic accumulation of anti-TRIM21 autoantibody immune complex in autoimmune disease.
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PMID:Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function. 1740 Jul 54

Human tRNALys3 is used as the primer for human immunodeficiency virus type 1 (HIV-1) reverse transcription. HIV-1 Gag and GagPol, as well as host cell factor lysyl-tRNA synthetase (LysRS), are required for specific packaging of tRNALys into virions. Gag alone is sufficient for packaging of LysRS, and these two proteins have been shown to interact in vitro with an equilibrium binding constant of approximately 310 nM. The capsid (CA) domain of Gag binds to LysRS with a similar affinity as full-length Gag. In this work, we report further characterization of the interaction between HIV-1 CA and human LysRS using truncation constructs and point mutations in the putative interaction helices. Fluorescence anisotropy binding measurements reveal that a LysRS variant lacking the N-terminal 219 residues still displays high affinity binding to CA. The CA C-terminal domain (CTD) is also sufficient for binding to LysRS. Nuclear magnetic resonance spectroscopy studies using 15N-labeled CA-CTD reveal chemical shift perturbations of residues in and proximal to helix 4 of CA-CTD upon LysRS binding. A synthetic peptide that includes helix 4 binds to LysRS with high affinity, whereas peptides derived from the other three helical domains of CA-CTD do not. Alanine-scanning mutagenesis studies targeting residues in the helix 4 region support a direct interaction between this domain of CA-CTD and LysRS. The high resolution mapping studies reported here will facilitate future work aimed at disrupting the Gag-LysRS interaction, which represents a novel anti-viral strategy.
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PMID:Critical role of helix 4 of HIV-1 capsid C-terminal domain in interactions with human lysyl-tRNA synthetase. 1772 17

A monoclonal Fab (Fab 3674) selected from a human nonimmune phage library by panning against the chimeric construct N(CCG)-gp41 (which comprises an exposed coiled-coil trimer of gp41 N helices fused in the helical phase onto the minimal thermostable ectodomain of gp41) is described. Fab 3674 is shown to neutralize diverse laboratory-adapted B strains of human immunodeficiency virus type 1 (HIV-1) and primary isolates of subtypes A, B, and C in an Env-pseudotyped-virus neutralization assay, albeit with reduced potency (approximately 25-fold) compared to that of 2F5 and 4E10. Alanine scanning mutagenesis maps a novel epitope to a shallow groove on the N helices of gp41 that is exposed between two C helices in the fusogenic six-helix bundle conformation of gp41. Bivalent Fab 3674 and the C34 peptide (a potent fusion inhibitor derived from the C helix of gp41) are shown to act at similar stages of the fusion reaction and to neutralize HIV-1 synergistically, providing additional evidence that the epitope of Fab 3674 is new and distinct from the binding site of C34.
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PMID:A monoclonal Fab derived from a human nonimmune phage library reveals a new epitope on gp41 and neutralizes diverse human immunodeficiency virus type 1 strains. 1789 46

Antibodies (Abs), often associated with antimicrobial and antitumor agents, have emerged as an important class of novel drugs for antigen-driven therapeutic purposes in diverse clinical settings, including oncology and infectious diseases. Abs commonly give rise in the treated host to anti-Ab responses, which may induce adverse reactions and limit their therapeutic efficacy. Their modular domain architecture has been exploited to generate alternative reduced formats (Fabs, scFvs, dAbs, minibodies, multibodies), essentially devoid of the Fc region. The presence of complementarity determining regions (CDRs) ensures the maintenance of selective binding to antigens and supports their use for biotechnological and therapeutic applications. Paradigmatic Abs mimicking the wide-spectrum antimicrobial activity of a yeast killer toxin (killer Abs) have revealed the existence of a family of Abs exerting a direct in vitro and/or in vivo microbicidal activity. Based on the variable sequence of an antiidiotypic recombinant killer Ab, CDR-related peptides have been synthesized, engineered by alanine-scanning and selected according to antimicrobial, antiviral and immunomodulatory properties. Irrespective of the native Ab specificity, synthetic CDRs from unrelated murine and human monoclonal Abs, have shown to display differential in vitro, in vivo and/or ex vivo antifungal (Candida albicans), antiviral (HIV-1) and antitumor (melanoma cells) activities. Alanine substitution of single residues of synthetic CDR peptides resulted in further differential increased/unaltered/decreased biological activity. The intriguing potential of Abs as source of antiinfective and antitumor therapeutics will be discussed, in light of recent advances in peptide design, stability and delivery.
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PMID:Antibodies as crypts of antiinfective and antitumor peptides. 1951 92

This study investigates the incidence of hepatotoxicity in HIV-infected children during anti-retroviral therapy (ART) and the impact of concomitant use of isoniazid preventive therapy. It is a retrospective cohort analysis of HIV-infected children who commenced ART or were followed up between September 1998 and November 2005. Alanine transferase levels were measured at baseline, at 1, 3 and 6 months and then 6 monthly thereafter. Of the 598 children included in the study, 425 were taking ART alone, 73 ART and isoniazid, 39 isoniazid alone and 61 neither isoniazid nor ART. There was no increased risk of hepatotoxicity with ART with or without isoniazid compared to the control group over a 2-year period. Grade 3 or 4 ALT elevations occurred in 19 (3.4%) children, with no cases of fulminant hepatic failure. Severe hepatic events are uncommon in children on ART or isoniazid. There is no increased risk of hepatotoxicity with ART and concurrent isoniazid preventive therapy.
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PMID:Low rates of hepatotoxicity in HIV-infected children on anti-retroviral therapy with and without isoniazid prophylaxis. 1971 Feb 46

The HIV-1 integrase protein (IN) mediates integration of the viral cDNA into the host genome and is a target for anti-HIV drugs. We have recently described a peptide derived from residues 361-370 of the IN cellular partner protein LEDGF/p75, which inhibited IN catalytic activity in vitro and HIV-1 replication in cells. Here we performed a comprehensive study of the LEDGF 361-370 mechanism of action in vitro, in cells and in vivo. Alanine scan, fluorescence anisotropy binding studies, homology modeling and NMR studies demonstrated that all residues in LEDGF 361-370 contribute to IN binding and inhibition. Kinetic studies in cells showed that LEDGF 361-370 specifically inhibited integration of viral cDNA. Thus, the full peptide was chosen for in vivo studies, in which it inhibited the production of HIV-1 RNA in mouse model. We conclude that the full LEDGF 361-370 peptide is a potent HIV-1 inhibitor and may be used for further development as an anti-HIV lead compound.
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PMID:Mechanism of action of the HIV-1 integrase inhibitory peptide LEDGF 361-370. 2017 Nov 72

The intracellular restriction factor TRIM5alpha, inhibits infection by numerous retroviruses in a species-specific manner. The best characterized example of this restriction is the TRIM5alpha protein from rhesus macaques (rhTRIM5alpha), which potently inhibits HIV-1 infection. TRIM5alpha localizes to cytoplasmic assemblies of protein referred to as cytoplasmic bodies, though the role that these bodies play in retroviral restriction is unclear. We employed a series of truncation mutants to identify a discrete region, located within the Linker2 region connecting the coiled-coil and B30.2/PRYSPRY domains of TRIM5alpha, which is required for cytoplasmic body localization. Deletion of this region in the context of full-length rhTRIM5alpha abrogates cytoplasmic body localization. Alanine mutagenesis of the residues in this region identifies two stretches of amino acids that are required for both cytoplasmic body localization and retroviral restriction. This work suggests that the determinants that mediate TRIM5alpha localization to cytoplasmic bodies play a requisite role in retroviral restriction.
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PMID:Identification of residues within the L2 region of rhesus TRIM5alpha that are required for retroviral restriction and cytoplasmic body localization. 2063 14

Therapies for immune thrombocytopenia (ITP) may be associated with abnormal hepatobiliary laboratory (HBL) values, but the epidemiology of these abnormalities is unknown in the ITP population. The study aim was to provide prevalence and incidence rates, as well as risk factors for abnormal HBL values among a cohort of patients with chronic or persistent primary ITP. Health insurance claims data from 3,244 patients with chronic or persistent ITP was examined to estimate the prevalence of abnormal HBL values: elevated levels of Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), total bilirubin, and Alkaline Phosphatase (ALP). Incidence of abnormal HBL values was estimated in a sub cohort of 2557 (79%) patients without evidence of comorbidities related to secondary thrombocytopenia, liver disease, or abnormal HBL values during the 12-month baseline period. The baseline prevalence of ALT and AST > 3x the upper limit of normal (ULN) was 4.6 and 3.7%, respectively. The baseline prevalence of total bilirubin and ALP >1.5x ULN was 4.2 and 3.2%, respectively. The incidence rate of new HBL abnormalities (HBLA) was 1.24/1,000 person-years (95% CI: 0.52-2.56) for ALT>3x ULN and 0.41/1,000 person-years (95% CI: 0.08-1.32) for AST>3x ULN. HBLAs were significantly associated with male gender, liver disease, diabetes, congestive heart failure, lupus, hematological cancers, and HIV infection. In conclusion, the prevalence of HBLA, specifically ALT>3x ULN, among the ITP population is relatively high compared with atrial fibrillation, though within the confidence interval for that estimate. HBLAs were significantly associated with male gender, liver disease, and several other comorbidities, thus, distinguishing drug-induced liver injury in this population is clinically challenging.
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PMID:Hepatobiliary laboratory abnormalities among patients with chronic or persistent immune thrombocytopenia (ITP). 2150 81


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