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)

Major histocompatibility complex class II HLA-DR molecules are plasma-membrane integral heterodimers, constitutively expressed in antigen-presenting cells. Their expression is known to be upregulated in peripheral T lymphocytes upon cell activation and to be constitutive in T cell lines. In H78-C10.0, a subclone of the human CD4+ T cell line HUT-78, the transport of MHC class II HLA-DR molecules is blocked, resulting in their localization within internal vesicular compartments rather than at the cell surface. In this article, we show that HIV-1(HX10) infection of H78-C10.0 cells induces HLA-DR surface expression. Moreover, the produced infectious viruses harbor the heterodimer molecules in their envelopes. To define which of the viral proteins was involved in this phenomenon, we infected H78-C10.0 cells with recombinant vaccinia vectors containing either the gag-pro coding sequence or the entire env gene. Only gag expression was able to induce HLA-DR cell-surface localization in H78-C10.0 cells. RT-PCR analysis of the infected cells revealed no significant alteration in the amount of HLA-DRalpha-specific RNA compared to untreated cells. This implies that Gag acts on downstream events. When the env viral gene, coding for the precursor glycoprotein gp160, was expressed in H78-C10.0, the Env protein targeted to the cell surface was poorly processed to its final mature forms gp120 and gp41. However, coexpression of the env and gag genes led to restoration of this phenotype. Although the mechanism is unknown, the data compiled in this study strongly suggest that the viral Gag protein can interact with the cellular trafficking apparatus. Moreover, in a specific cell type as H78-C10.0 this interaction can even reverse intracellular transport defects.
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PMID:HIV-1 gag polyprotein rescues HLA-DR intracellular transport in a human CD4+ cell line. 1220 16

The envelope glycoprotein of HIV-2 ROD10 has the intriguing ability to enhance the rate of viral particle release from infected cells. However, not all HIV-2 envelope glycoproteins are active in this regard. Indeed, we have previously noted that, despite a high degree of identity with that of ROD10, the envelope protein of the ROD14 isolate was unable to enhance virus production. In this study, site-directed mutagenesis was employed to reveal that a single naturally occurring alanine-to-threonine substitution at position 598, located in the extracellular part of the TM subunit, fully accounted for the lack of activity of the ROD14 Env in HeLa and 12D7 cells. A second mutation at position 422, substituting a lysine residue in ROD10 for an arginine in ROD14, was additionally required for efficient virus release from infected H9 cells, suggesting cell-type-specific requirements for this activity. Interestingly, the ROD14 Env protein exhibited a trans-dominant negative effect on particle release by ROD10 Env, suggesting that the viral release activity of the HIV-2 ROD envelope protein may be regulated by its ability to assemble into functional oligomeric structures.
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PMID:Naturally occurring amino acid substitutions in the HIV-2 ROD envelope glycoprotein regulate its ability to augment viral particle release. 1272 29

An effective vaccine against AIDS should induce both cellular and humoral immune responses. Here we report that immunization of mice with a DNA plasmid encoding a chimeric protein consisting of HIV89.6 Env gp140 and the listeriolysin O (LLO) C-terminal segment (59 amino acids) significantly enhanced both humoral and cellular immune responses against the HIV89.6 Env protein. Plasmid DNA expression vectors with genes codon-optimized for mammalian expression were synthesized for HIV89.6 gp140 as well as for chimeric protein gp140-LLO, in which the coding sequence for the C-terminal 59 amino acids of LLO were fused in frame to the 3' end of the codon-optimized gene for gp140. All plasmid vectors produced high levels of protein expression, and the gp140-LLO chimeric protein was cleaved and secreted as efficiently as gp140. Analysis of humoral immune responses by ELISA showed that the chimeric gp140-LLO construct induced higher antibody responses than the gp140 construct in immunized mice, more notably in the IgG2a antibody subtype. Intracellular cytokine staining and flow cytometry analysis showed that the gp140-LLO construct induced significantly higher levels of cytotoxic T lymphocyte immune responses against the HIV 89.6 Env protein than those observed with the gp140 construct. Our results thus demonstrate that the C-terminal segment of LLO can be effectively employed to enhance both cellular and humoral immune responses against the HIV89.6 Env antigen in the context of a DNA vaccine.
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PMID:Enhancement of immune responses to an HIV env DNA vaccine by a C-terminal segment of listeriolysin O. 1280 99

To enhance mucosal immune responses using simian/human immunodeficiency virus-like particles (SHIV VLPs), we have produced novel phenotypically mixed chimeric influenza HA/SHIV VLPs and used them to immunize C57BL/6J mice intranasally. Antibody and cytotoxic T-cell (CTL) responses as well as cytokine production in both systemic and mucosal sites were compared after immunization with SHIV VLPs or chimeric HA/SHIV VLPs. By using enzyme-linked immunosorbent assay (ELISA), the levels of serum IgG and mucosal IgA to the HIV envelope protein (Env) were found to be highest in the group immunized with chimeric HA/SHIV VLPs. Furthermore, the highest titer of serum neutralizing antibody against HIV Env was found with the group immunized with chimeric HA/SHIV VLPs. Analysis of the IgG1/IgG2a ratio indicated that a T(H)1-oriented immune response resulted from these VLP immunizations. HA/SHIV VLP-immunized mice also showed significantly higher CTL responses than those observed in SHIV VLP-immunized mice. Moreover, a MHC class I restricted T-cell activation ELISPOT assay showed a mixed type of T(H)1/T(H)2 cytokines in the HA/SHIV VLP-immunized mice, indicating that the chimeric VLPs can enhance both humoral and cellular immune responses to the HIV Env protein at multiple mucosal and systemic sites. The results indicate that incorporation of influenza HA into heterotypic VLPs may be highly effective for targeting vaccines to mucosal surfaces.
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PMID:Enhancement of mucosal immune responses by chimeric influenza HA/SHIV virus-like particles. 1295 17

For HIV-1 to enter a cell, its envelope protein (Env) must sequentially engage CD4 and a chemokine coreceptor, triggering conformational changes in Env that ultimately lead to fusion between the viral and host cell membranes. Each step of the virus entry pathway is a potential target for novel antiviral agents termed entry inhibitors. A growing number of entry inhibitors are under clinical development, with one having already been licensed by the Food and Drug Administration. With the emergence of virus strains that are largely resistant to existing reverse transcriptase and protease inhibitors, the development of entry inhibitors comes at an opportune time. Nonetheless, because all entry inhibitors target in some manner the highly variable Env protein of HIV-1, there are likely to be challenges in their efficient application that are unique to this class of drugs. Env density, receptor expression levels, and differences in affinity and receptor presentation are all factors that could influence the clinical response to this promising class of new antiviral agents.
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PMID:The entry of entry inhibitors: a fusion of science and medicine. 1296 Mar 67

Rabies virus (RV) vaccine strain-based vectors show significant promise as potential live-attenuated vaccines against human immunodeficiency virus type 1 (HIV-1). Here we describe a new RV construct that will also likely have applications as a live-attenuated or killed-particle immunogen. We have created a RV containing a chimeric HIV-1 Env protein, which contains introduced cysteine residues that give rise to an intermolecular disulfide bridge between gp120 and the ectodomain of gp41. This covalently linked gp140 (gp140 SOS) is fused in frame to the cytoplasmic domain of RV G glycoprotein and is efficiently incorporated into the RV virion. On the HIV-1 virion, the gp120 and gp41 moieties are noncovalently associated, which leads to extensive shedding of gp120 from virions and virus-infected cells. The ability to use HIV-1 particles as purified, inactivated immunogens has been confounded by the loss of gp120 during preparation. Additionally, monomeric gp120 and uncleaved gp160 molecules have been shown to be poor antigenic representations of virion-associated gp160. Because the gp120 and gp41 portions are covalently attached in the gp140 SOS molecule, the protein is maintained on the surface of the RV virion throughout purification. Surface immunostaining and fluorescence-activated cell sorting analysis with anti-envelope antibodies show that the gp140 SOS protein is stably expressed on the surface of infected cells and maintains CD4 binding capabilities. Furthermore, Western blot and immunoprecipitation experiments with infected-cell lysates and purified virions show that a panel of neutralizing anti-envelope antibodies efficiently recognize the gp140 SOS protein. The antigenic properties of this recombinant RV particle containing covalently attached Env, as well as the ability to present Env in a membrane-bound form, suggest that this approach could be a useful component of a HIV-1 vaccine strategy.
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PMID:Covalently linked human immunodeficiency virus type 1 gp120/gp41 is stably anchored in rhabdovirus particles and exposes critical neutralizing epitopes. 1461 Feb

DNA vaccines expressing the envelope (Env) of human immunodeficiency virus type 1 (HIV-1) have been relatively ineffective at generating high-titer, long-lasting immune responses. Oligomeric or trimeric (gp140) forms of Env that more closely mimic the native proteins on the virion are often more effective immunogens than monomeric (gp120) envelopes. In this study, several forms of Env constructed from the HIV-1 isolate YU-2 (HIV-1(YU-2)) were tested for their immunogenic potential: a trimeric form of uncleaved (-) Env stabilized with a synthetic trimer motif isolated from the fibritin (FT) protein of the T4 bacteriophage, sgp140(YU-2)(-/FT), was compared to sgp140(YU-2)(-) without a synthetic trimerization domain, as well as to monomeric gp120(YU-2). DNA plasmids were constructed to express Env alone or fused to various copies of murine C3d (mC3d). BALB/c mice were vaccinated (day 1 and week 4) with DNA expressing a codon-optimized envelope gene insert, alone or fused to mC3d. Mice were subsequently boosted (week 8) with the DNA or recombinant Env protein. All mice had high anti-Env antibody titers regardless of the use of mC3d. Sera from mice vaccinated with DNA expressing non-C3d-fused trimers elicited neutralizing antibodies against homologous HIV-1(YU-2) virus infection in vitro. In contrast, sera from mice inoculated with DNA expressing Env-C3d protein trimers elicited antibody that neutralized both homologous HIV-1(YU-2) and heterologous HIV-1(ADA), albeit at low titers. Therefore, DNA vaccines expressing trimeric envelopes coupled to mC3d, expressed in vivo from codon-optimized sequences, elicit low titers of neutralizing antibodies against primary isolates of HIV-1.
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PMID:Elicitation of neutralizing antibodies with DNA vaccines expressing soluble stabilized human immunodeficiency virus type 1 envelope glycoprotein trimers conjugated to C3d. 1507 53

Xenotransplantation of pig organs may be associated with a risk of transmission of microorganisms. Porcine endogenous retroviruses (PERV) are of particular concern since in vitro experiments have demonstrated that human cells are susceptible to such microorganisms. To monitor the transmission of PERV, highly sensitive and specific immunoassays must be developed for clinical surveillance. This report describes the production, preliminary characterization and application of a monoclonal antibody (mAb) against a recombinant PERV envelope (Env) protein. The generated mAb was tested using recombinant PERV Env protein expressed in Escherichia coli, purified PERV virus particles and human 293 cell line infected with PERV. PERV-translated proteins of 15, 70 and 85 kD were recognized specifically using PERV-8E10 mAb and Western blotting. No cross-reactivity was demonstrated with exogenous viral protein (HIV, HTLV and MuLV). Moreover, PERV-8E10 mAb can be applied to localize PERV proteins using an immunoperoxidase assay. This work reveals that recombinant PERV Env protein and mAb may be effective in detecting antibodies against PERV in xenotransplanted patients, or for butchers who have extensive contact with pigs.
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PMID:Establishing the reactivity of monoclonal antibodies against porcine endogenous retrovirus envelope protein. 1519 73

Neutralizing antibody titers have been correlated with protection following vaccination against many viral pathogens. The logical target of protective antibody responses elicited by potential HIV vaccines should be the viral Env spike on the surface of the virion. However, the potency and titers of neutralizing antibodies that arise during HIV infection are generally discouragingly low and the antibodies that do arise recognize mainly autologous virus. This is thought to be a result of a combination of immunodominance of hypervariable regions of the Env protein that can easily escape neutralization, antibody reactivity to gp160 "decoy" protein in cell surface debris or monomeric gp120, conformational constraints within the Env trimer that create unfavorable antibody binding conditions and extensive glycosylation of the exposed regions of Env within the trimer. This review will describe current knowledge regarding glycosylation as a mechanism of neutralization resistance and discuss experimental approaches used to overcome this resistance. Part of the strategy toward development of an optimally immunogenic Env spike will likely require modification of Env glycosylation.
Curr HIV Res 2004 Jul
PMID:Glycosylation of the ENV spike of primate immunodeficiency viruses and antibody neutralization. 1527 88

The effects of two functional domains, the membrane-proximal YXXPhi motif and the membrane-distal inhibitory sequence in the long cytoplasmic tail of the human immunodeficiency virus type 1 (HIV-1) envelope protein (Env), on immunogenicity of the envelope protein were investigated. Genes with codons optimized for mammalian expression were synthesized for the HIV 89.6 Env and a truncated Env with 50 amino acids in the cytoplasmic domain to delete the membrane distal inhibitory sequence for surface expression. Additional genes were generated in which the tyrosine residue in the YXXPhi motif was changed into a serine. Pulse-chase radioactive labeling and immunoprecipitation studies indicated that both domains can mediate endocytosis of the HIV Env, and removal of both domains is required to enhance HIV Env protein surface stability. Analysis of immune responses induced by DNA immunization of mice showed that the DNA construct for the mutant Env exhibiting enhanced surface stability induced significantly higher levels of antibody responses against the HIV Env protein. Our results suggest that the HIV Env cytoplasmic domain may play important roles in virus infection and pathogenesis by modulating its immunogenicity.
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PMID:Surface stability and immunogenicity of the human immunodeficiency virus envelope glycoprotein: role of the cytoplasmic domain. 1556 51


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