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Query: UMLS:C0001175 (AIDS)
 120,706 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retroviral nucleocapsid (NC) proteins are highly basic, with one or two zinc fingers, and are required for virion formation, genomic RNA dimerization and packaging, and replication primer tRNA annealing to the viral RNA. We report here the first characterization of monoclonal antibodies directed against a retroviral nucleocapsid protein and their use to study the structure-function relationships of the nucleocapsid protein NCp7 of HIV-1. Four anti-NCp7 monoclonal antibodies (MAbs) have been generated by using NCp7 of HIV-1. The epitope targets of these MAbs were mapped using ELISA and BIAcore techniques. Whereas three of them are specific for epitopes located in the N and C termini of NCp7, the fourth one appears to be conformation specific. Interestingly, only two of these MAbs, the conformation-specific one and the MAb recognizing an N-terminal epitope are able to inhibit the RNA-binding and annealing activities of NCp7 as well as strong-stop DNA synthesis in vitro. The binding of the two other MAbs onto NCp7 either has no effect or enhances the NCp7-RNA interactions. These MAbs also display a differential recognition of the Gag polyprotein precursor, which makes them useful tools for studying NC protein maturation in the course of virion morphogenesis.
AIDS Res Hum Retroviruses 1994 Aug
PMID:Monoclonal antibody-mediated inhibition of RNA binding and annealing activities of HIV type 1 nucleocapsid protein. 752 35

T epitope mapping in human immunodeficiency virus proteins provides a useful tool for AIDS vaccine design. We have previously shown that four peptides selected from the Gag polyprotein of HIV-1 were able to prime mice for in vitro lymphoproliferative responses. These responses were shown to be MHC restricted, and a pool of these peptides was able to prime mice for a subsequent humoral response to HIV-1 Gag proteins. Here we show that two of these Gag peptides are able to prime the anti-HIV-1 IgG response to heat-inactivated HIV-1 in B10Sc.Cr mice. Furthermore, we extended this study in the nonhuman primate model, and show efficient priming of the IgG response to heat-inactivated HIV-1 using the pool of four Gag peptides in baboons. Further mapping of "nonself" peptides is extended to the HIV-1 Nef protein. Three potential Nef T epitopes located at positions 137-145, 98-107, and 81-95 are also shown to prime the IgG response to HIV-1 in the mouse model, although T cell proliferation to recall peptides in vitro was not detectable. Although they have not yet been defined as major helper T epitopes in humans, using classic in vitro stimulation assays, the fact that most of them are able to prime IgG responses in animals without detectable in vitro proliferative responses does not rule out their functional helper capacity in humans.
AIDS Res Hum Retroviruses 1994 Oct
PMID:Nef and Gag synthetic peptide priming of antibody responses to HIV type 1 antigens in mice and primates. 753 60

Productive, spreading infection of peripheral blood lymphocytes (PBL) with human immunodeficiency virus type 1 (HIV-1) requires the viral protein Vif. To study the requirement for vif in this system, we infected PBL with a phenotypically complemented HIV-1 clone mutated in vif. Progeny virus was produced which was noninfectious in PBL but replicated in SupT1 cells. Analysis of metabolically labeled proteins of sedimentable extracellular particles made in PBL by radioimmunoprecipitation with either serum from a patient with AIDS or a monoclonal antibody reactive with HIV-1 Gag proteins revealed that vif-negative but not wild-type particles carry higher levels of p55, p41, and p38 Gag-specific proteins compared with those of p24. Similar results were obtained with sucrose-purified virions. Our data indicate that vif plays a role in Gag protein processing or in incorporation of processed Gag products into mature virions. The presence of unprocessed precursor Gag polyprotein (Pr55gag) and other Gag processing intermediates in PBL-derived vif-negative extracellular particles may contribute to the reduced infectivity of this virus.
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PMID:Aberrant Gag protein composition of a human immunodeficiency virus type 1 vif mutant produced in primary lymphocytes. 776 28

Among murine leukemia viruses (MuLV) present in the LP-BM5 virus mixture, the agent etiologic for an acquired immunodeficiency syndrome (MAIDS) is replication defective, containing only a single open reading frame which includes all of gag. The Gag polyprotein encoded by the defective virus, termed BM5def, differs most in p12 from that of nonpathogenic ecotropic virus (BM5eco). As one approach to examining the role of p12 in disease, the ecotropic and defective virus forms of the protein, synthesized in bacteria, were used to immunize three strains of mice differing in their sensitivity to MAIDS. In each strain, both proteins elicited substantial antibody responses that were cross-reactive with either p12 and recognized the proteins as part of intact viral Gag polyproteins. Immunization with either p12 before infection with LP-BM5 viruses had no effect on the sensitivity or resistance of mice to MAIDS or on the extent of helper virus spread. The variant p12 of BM5def, when presented on its own, is thus not a crucial antigenic determinant of disease. Alternative mechanisms by which BM5def may contribute to MAIDS are discussed.
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PMID:Effects of immunization with the p12 proteins of LP-BM5 defective and ecotropic viruses on development of MAIDS. 838 12

Foamy viruses are a genus of complex retroviruses that infect a wide variety of mammals. However, a clear association with any disease process has yet to be proven for these viruses. A higher human seroprevalence was reported in African populations, perhaps due to exposure to simian foamy viruses (SFV) endemic in primates. However, the earlier serologic surveys were not confirmed by studies employing nucleic acid amplification. Foamy virus infections of humans clearly do occur as rare zoonoses among primate center or laboratory workers exposed to captive primates or their blood. We sought to detect foamy virus infections in a cohort of humans also presumed to be exposed to SFV, i.e., West African hunters. We constructed recombinant vaccinia viruses that expressed human foamy virus (HFV) Gag or Env polyproteins in mammalian cells. The sera from 17 monkey hunters or several controls were tested in radioimmunoprecipitation assays (RIPAs) against the recombinant HFV proteins. Chimpanzee sera or HFV-positive human sera immunoprecipitated gp130, the HFV Env precursor, as well as p74, the HFV Gag polyprotein. None of the hunters' sera recognized both of these recombinant proteins. We then employed a nested polymerase chain reaction (PCR) analysis of the hunters' DNA but also failed to detect foamy virus infections. Therefore, by utilizing a recombinant RIPA and a nested PCR assay, we have not identified foamy virus infections occurring naturally in hunters exposed to wild monkeys in West Africa.
AIDS Res Hum Retroviruses 1996 Dec 10
PMID:Analysis of west African hunters for foamy virus infections. 895 50

The unique Gag polyprotein of the replication-defective virus responsible for murine AIDS (MAIDS) induces B-cell activation, proliferation, and differentiation, including immunoglobulin class switch-recombination to immunoglobulin E (IgE). Secretion of IgE normally requires the serial induction of interleukin 4 (IL-4), engagement of the IL-4 receptor, activation of signal transducer and activator of transcription (STAT) 6, and induction of Iepsilon germline transcripts as a prelude to switching. Remarkably, expression of IgE is equivalent in normal and IL-4-deficient mice with MAIDS (Morawetz et al., J. Exp. Med. 184:1651-1661, 1996). To understand this anomaly, we studied mice with a null mutation of STAT6. Lymphoproliferation and immunodeficiency, the hallmarks of MAIDS, developed with comparable kinetics and degree in normal and mutant mice. In addition, serum IgE levels were indistinguishable in mice of either genotype. We conclude that B cells from mice with MAIDS activate unique IL-4- and STAT6-independent signaling pathways for B-cell activation and differentiation.
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PMID:STAT6-deficient mice exhibit normal induction of murine AIDS and expression of immunoglobulin E following infection with LP-BM5 murine leukemia viruses. 1040 Aug 16

The HIV-1 NCp7 contains two spatially close zinc fingers, required for the production of infectious particles. To investigate in more detail the function of the zinc finger domain, monoclonal antibodies were generated with a cyclic analog of the NCp7 proximal zinc finger. This analog was shown to bind zinc ions and to preserve the highly folded structure of the native peptide (Dong C-Z et al.: J Am Chem Soc 1995;117:2726-2731). We report here two monoclonal antibodies (2B10 and 4D3), which are the first monoclonal antibodies directed against CCHC NCp7 zinc fingers. Dot-blot experiments revealed that a few nanograms of synthetic NCp7 can be detected on a nitrocellulose membrane. Whereas 2B10 appears specific for an epitope located in sequence 19-27 of NCp7, 4D3 appears to be structurally specific. Immunocomplex affinities were evaluated, using BIAcore technology, to be up to 1 and 10 nM, respectively, for 2B10 and 4D3 in 100 mM NaCl. These antibodies were able to recognize NCp7 in the Gag polyprotein precursor and were shown to immunoprecipitate NCp7 from a cell supernatant. Moreover, NCp7-Vpr interaction mediated by the zinc fingers is inhibited by 2B10, emphasizing the role of these domains in the protein-protein complex. These results indicate that 2B10 and 4D3 behave as useful tools for studying both NC protein functions during the course of virion morphogenesis and the role played by its zinc finger domain at various steps in the retroviral life cycle.
AIDS Res Hum Retroviruses 2000 Sep 01
PMID:Generation of monoclonal antibodies specifically directed against the proximal zinc finger of HIV type 1 NCp7. 1095 23

In human cells infected by HIV type 1 (HIV-1), the viral Gag protein directs the assembly of nascent viral particles at the plasma membrane. In murine cells, HIV-1 Gag fails to reach the plasma membrane and instead forms nonfunctional intracellular aggregates. The viral determinants of this species incompatibility are previously undefined. To address this problem, we replaced a region of HIV-1 Gag known to direct its localization, the matrix (MA) domain, with functionally homologous regions from Moloney murine leukemia virus (MLV), a murine retrovirus. An HIV-1 clone carrying such a chimeric Gag protein, designated murine HIV (MHIV), assembled more efficiently than nonchimeric HIV-1 and restored plasma membrane localization of Gag in murine cells. Increased efficiency of viral assembly in murine cells was observed from MHIV constructs carrying MLV MA in place of HIV-1 MA. Efficient processing of the HIV-1 capsid protein from the chimeric Gag polyprotein and subsequent infectivity of MHIV required the presence of MLV p12 in addition to MLV MA. These findings strongly suggest that the HIV-1 MA domain of HIV-1 Gag is responsible for the assembly defect in mouse cells. Although these MHIV do not recruit native HIV-1 Env efficiently, they are capable of single-round infection when produced by high-efficiency transfection of human 293 cells and provided with an HIV-1 Env lacking its cytoplasmic tail. With further adaptation, this chimeric MHIV approach may provide the basis for creating an infectious mouse model for HIV/AIDS.
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PMID:Efficient assembly of an HIV-1/MLV Gag-chimeric virus in murine cells. 1174 97

During the assembly stage of the human immunodeficiency virus (HIV) replication cycle, several thousand copies of the viral Gag polyprotein associate at the cell membrane and bud to form an immature, non-infectious virion. Gag is subsequently cleaved by the protease, which liberates the capsid proteins for assembly into the polyprotein shell of the central core particle (or capsid) of the mature virus. Viral infectivity is critically dependent on capsid formation and stability, making the capsid protein a potentially attractive antiviral target. We have identified compounds that bind to an apical site on the N-terminal domain of the HIV-1 capsid protein and inhibit capsid assembly in vitro. One compound, N-(3-chloro-4-methylphenyl)-N'-[2-[([5-[(dimethylamino)-methyl]-2-furyl]-methyl)-sulfanyl]ethyl]urea) (CAP-1), is well tolerated in cell cultures, enabling in vivo antiviral and mechanistic studies. CAP-1 inhibits HIV-1 infectivity in a dose-dependent manner, but does not interfere with viral entry, reverse transcription, integration, proteolytic processing, or virus production, indicating a novel antiviral mechanism. Significantly, virus particles generated in the presence of CAP-1 exhibit heterogeneous sizes and abnormal core morphologies, consistent with inhibited CA-CA interactions during virus assembly and maturation. These findings lay the groundwork for the development of assembly inhibitors as a new class of therapeutic agents for the treatment of AIDS.
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PMID:Antiviral inhibition of the HIV-1 capsid protein. 1266 26

The Gag polyprotein of retroviruses and lentiviruses is the master orchestrator of viral particle formation. HIV-1 Gag is synthesized on cytosolic polysomes where it is co-translationally modified with the 14-carbon fatty acid myristate. New findings shed light on how myristoylated HIV-1 Gag traffics through the cell, binds to specific membranes, and assembles into virions. The affinity of Gag for membrane bilayers is regulated by a myristoyl switch; Gag multimerization induces the fatty acid to flip away from the protein, thereby promoting membrane binding during assembly. Several recent studies have shown that newly synthesized Gag traffics first to multivesicular bodies (MVB), endosomal compartments that contain protein complexes necessary for particle budding. Signals within Gag, as well as specific host-cell lipids and proteins, promote MVB localization. In macrophages, Gag is retained in MVBs; viral particles are formed within the MVB lumen and released from the cell via exocytosis. In other cell types, Gag and/or MVBs rapidly transit to the plasma membrane where particle release occurs. Given that MVB exocytosis is an essential host-cell pathway, effective antiviral agents will need to specifically target interaction of Gag with the endocytic pathway without perturbing the normal host-cell trafficking network.
AIDS Rev
PMID:Intracellular trafficking of HIV-1 Gag: how Gag interacts with cell membranes and makes viral particles. 1609 2


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