Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have cloned the simian foamy virus type 1 genome (SFV1) and determined its nucleotide sequence. Analysis of this genome reveals, in addition to the usual genes encoding retroviral capsid, reverse transcriptase, and envelope protein (respectively, gag, pol, and env), two open reading frames (ORFs) between env and the long terminal repeat with partial homology to the human foamy virus (HFV) bel1 and bel2 genes. The first ORF could code for a polypeptide of 312 amino acids (aa) showing 40% homology with the HFV bel1 putative gene product. A more detailed analysis showed that the protein encoded by this ORF would have features characteristic of known trans-activating proteins. The second ORF could code for a polypeptide of 403 aa showing 38% homology with the putative HFV bel2 gene product. Moreover, the 5' extremity of the RNA genome can be folded into a secondary structure identical to the Tat-response element of human immunodeficiency viruses. A phylogenetic tree of retroviruses, including SFV1 and HFV, was constructed. It showed at the molecular level that Spumavirinae, previously classified on the basis of their morphology and their biological properties, constitute a separate group. The homology between SFV1 and HFV reaches 89% in the reverse transcriptase domain of the pol gene. but is much smaller in other parts of the genome.
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PMID:Sequence analysis of the simian foamy virus type 1 genome. 164 58

This study describes the derivation of a series of mutants from the human leukemic cell line CEM using the frame shift mutagen Ethyl-methanesulfonate followed by negative selection with multiple treatments of OKT4A + C, and sorting into CD4-, CD4-dull, and CD4-intermediate mutants. These mutants express reduced CD4 levels ranging from 0 to 60% of the parental line. The mutants were analyzed by staining with a battery of CD4-specific mAb, by assessing their ability to bind soluble gp120, and by their ability to form syncytia after infection with cell-free HIV I virus and a gp160-vaccinia vector. Two groups of particularly interesting mutants were identified: (1) CD4-dull mutants expressing only 5 to 10% of the wild type surface CD4 density, which nevertheless were infectable by HIV I and produced as many syncytia and reverse transcriptase activity as the parental line after infection with gp160-vaccinia or cell free HIV I. (2) CD4-intermediate mutants (30 to 60% of parental CD4 level), which express CD4-epitopes required for interaction with the HIV I envelope protein, yet are markedly deficient in their ability to form syncytia after gp160-vaccinia or HIV I infection. Two of these mutants did form syncytia after transient reconstitution with a wild type CD4 containing vaccinia vector. Inasmuch as they were found to bind soluble gp120 with the same avidity as other, functionally normal, CD4-intermediate mutants, these human T cell mutants may have a reduced susceptibility to HIV I infection due to the absence of a "fusogenic component" or to a structural alteration in a region of the CD4 molecule not required for binding of the HIV I envelope, but for the subsequent fusion and entry process.
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PMID:Chemically induced CD4 mutants of a human T cell line. Evidence for dissociation between binding of HIV I envelope and susceptibility to HIV I infection and syncytia formation. 169 Feb 35

As human immunodeficiency virus type 1 (HIV-1) has become better understood, numerous drugs have been developed that act at virus-specific sites. These are challenging our ability to evaluate them thoroughly and rapidly. Zidovudine (AZT) remains the mainstay of anti-HIV-1 drugs. Recent controlled trials indicate it should be used early in infection (in those with CD4 cell counts less than 500/mm3) and in lower doses (500-600 mg/day). Prolonged AZT treatment in patients with AIDS, however, is often associated with viral resistance. Newer reverse transcriptase-inhibiting nucleoside derivatives are currently in phase II-III clinical trials. Other HIV-1 replicative sites under attack in clinical studies include binding and entry of virus, envelope protein glycosylation, and viral assembly and release. Agents that target HIV-1 proteinase, integrase, ribonuclease H, and products of regulatory genes such as tat are under development. Combination therapies that target different viral replicative sites likely will allow use of individual agents below their toxic concentrations and help prevent drug resistance. Innovative programs for expanded access to experimental drugs are needed that will permit expeditious clinical trials, optimize the gathering of useful information, and permit the widest access to promising treatments.
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PMID:Chemotherapy of human immunodeficiency virus infections: current practice and future prospects. 169 Dec 43

Duck hepatitis B virus mutants containing frameshift or stop codon mutations in a portion of the viral pol gene separating the terminal protein and reverse transcriptase domains had a leaky phenotype and, depending on the location and type of mutation, synthesized up to 10% as much viral DNA as did the wild type. This region of the pol gene had previously been reported to be refractory to missense mutations; in fact, the leakiness of most of our mutants appeared attributable to translational suppression, which would also be expected to introduce amino acid changes. However, at least one mutant (pH1093 + 2), which was ca. 10% as active as the wild type, appeared to use a novel pathway to express the viral pol gene. Our analyses indicated that pH1093 + 2 synthesized the viral reverse transcriptase as a fusion protein with the amino-terminal portion of the pre-S envelope protein. Thus, in this case, the products of the terminal-protein and reverse transcriptase domains of the pol gene would function as separate protein species, though perhaps noncovalently joined in a dimeric structure during assembly of DNA replication complexes. Evidence was also obtained that was consistent with the idea that the wild-type pol gene may, at least in certain instances, be expressed as functional, subgenic polypeptides.
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PMID:Evidence that less-than-full-length pol gene products are functional in hepadnavirus DNA synthesis. 170 80

In addition to their properties as sequence-specific inhibitors of gene expression, sequence nonspecific phosphorothioate oligodeoxynucleotides have been shown to protect against the cytopathic effects of HIV-1. Although these compounds are effective inhibitors of HIV-1 reverse transcriptase in vitro, it is not certain that they exert their cytoprotective effect only in this manner. Initial binding of the HIV-1 virion to cells involves the interaction of the viral envelope protein gp120 with CD4. In this report, we describe flow cytometric data and a solid-phase ELISA assay that document the ability of a phosphorothioate deoxycytidine 28-mer to interfere with this interaction by competing with gp120 binding to CD4. The biological importance of this interaction is demonstrated by the fact that phosphorothioate oligodeoxycytidine inhibits syncytium formation resulting from HIV-1-induced cell fusion. These data suggest that phosphorothioate oligodeoxynucleotides may exert their cytoprotective effects, perhaps at least in part, by interfering with the binding of HIV-1 to the target cells.
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PMID:Phosphorothioate oligodeoxycytidine interferes with binding of HIV-1 gp120 to CD4. 171 Nov 18

Design of a synthetic vaccine for HIV requires basic knowledge of the structure of helper and cytotoxic T-cell epitopes and neutralizing antibody epitopes, of ways to couple these to produce an effective immunogen, and of the role of viral sequence variation on MHC presentation of antigen. T-cell recognition, and cross-reactivity. We have been addressing all these issues for the HIV envelope and more recently also for the reverse transcriptase. We have now identified antigenic sites or epitopes from HIV envelope and reverse transcriptase recognized by cytotoxic T cells from both mice and humans in association with murine class I H-2 and human class I HLA antigens, as well as epitopes recognized by helper T cells in association with class II MHC molecules from both mice and humans. We have identified residues affecting interaction of peptides with MHC molecules and T-cell receptors and have examined the role of viral variability on presentation of these peptides by MHC molecules and recognition by T cells. One CTL epitope peptide was found to be presented by class II MHC molecules as well as class I MHC molecules and to be able to elicit CD4+ helper cells to aid in the induction of CD8+ CTL against the same peptide. One of the helper epitope peptides has been shown to be a powerful carrier for inducing neutralizing antibodies, and we have shown in rhesus monkeys that some of these helper peptides are immunogenic in primates and can elicit helper T cells that greatly augment the antibody response to a challenge in vivo with a suboptimal dose of HIV envelope protein compared to monkeys not given peptides, as one would want a vaccine to do. We have also identified multideterminant regions of the HIV-1 envelope and have made peptides corresponding to these that elicit helper T-cell responses in a large fraction of mouse strains and of outbred humans, as an approach to overcoming the problem of genetic restriction of T-cell responses. We have also developed a way of using purified recombinant proteins to elicit cytotoxic T cells in vivo by immunizing with the proteins incorporated into ISCOMs, and this method could be applied to an artificial vaccine as well. Some of these peptides should be candidates for immunotherapy trials in HIV-infected humans, as well as for vaccine development and diagnostic use.
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PMID:Progress toward an artificial vaccine for HIV: identification of helper and cytotoxic T-cell epitopes and methods of immunization. 172 61

Acquired immune deficiency syndrome (AIDS) is caused by infection with the human immunodeficiency virus (HIV), a human retrovirus. The virus infects cells of the immune system by attachment of a glycoprotein viral envelope (gp 120) to a molecule expressed on human helper T cells called CD4. The fusion of the virus envelope protein to its specific receptor allows HIV to penetrate the T cell. Once inside the cell viral RNA is transcribed into double-stranded DNA by an enzyme unique to retroviruses, reverse transcriptase. The double-stranded, proviral DNA travels to the nucleus of the cell and is integrated into the infected cell's chromosomal DNA where it may remain latent for years. As a result of triggers that are poorly understood, viral replication becomes activated and proviral DNA is transcribed back into genomic RNA and RNA that is translated into viral proteins, both of which are packaged and bud from the infected T cell as infectious virus. The viral life cycle orchestrates the natural history of clinical HIV infection. Three to four weeks following exposure to HIV there is a phase of rapid viral replication, high levels of plasma viremia, and development of a "flue like" illness. Four to six weeks after exposure, during this stage of acute infection, antibodies to HIV core (p24) and envelope (gp 160, gp 120, gp41) proteins appear. Six to eight weeks after exposure symptoms disappear and plasma viremia subsides, presumably due to clearance by the immune system.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pathogenesis and natural history of HIV infection. 175 33

Deletions were constructed within a functional human immunodeficiency virus type 1 (HIV-1) proviral clone in order to assess the role of the envelope protein in virus particle formation. A graded exonuclease deletion technique was used to produce 12 clones with deletions of 175-308 nucleotides in the first conserved domain of envelope. This included 9 clones with frameshift deletions and 3 clones with in-frame deletions. Isogenic pairs of env deletion clones were produced with or without an additional deletion in the vif and vpr genes. Upon transfection, all clones produced virus particles, as determined by p24 antigen, reverse transcriptase, and sucrose gradient assays with conditioned media. Virus particles produced from clones with deletions in env or vif and vpr, or both regions, banded on sucrose gradients with a mobility similar to that of virus produced by the parental clone. The p24 gag capsid protein in the particles was resistant to trypsin, but the particles were disrupted by treatment with Triton X-100, suggesting the presence of a surrounding lipid bilayer. Furthermore, electron microscopic studies revealed both mature and immature virus particles derived from COS cells transfected with the env deletion clones. Cocultivation experiments with lymphoid cells and cells transfected with each of the env deletion clones demonstrated that the virus particles were noninfectious.
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PMID:Formation of noninfectious HIV-1 virus particles lacking a full-length envelope protein. 182 17

This article outlines steps in the development of antiviral drugs, with particular emphasis on therapeutic regimens for infections with human T-lymphotropic virus type III (HTLV-III). Inhibitors of reverse transcriptase activity, including suramin, antimoniotungstate (HPA-23), and trisodium phosphonorformate have shown in vitro activity against HTLV-III in early clinical trials. Other significant antiviral agents are recombinant interferon alpha-A, ribavirin, and ansamycin. Recent evidence suggests that antibodies to envelope protein, gp120, may be essential for neutralization. Combinations of antiviral agents may prove additive or synergistic, eg, interferons plus reverse transcriptase inhibitors or interferons plus ribavirin. Alternating, sequential antiviral regimens may be useful in reducing resistance and toxicity. However, antiviral agents will not be effective without additonal immunostimulatory therapy for viral control and immune reconstitution.
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PMID:Prospects of therapy for infections with human T-lymphotropic virus type III. 241 93

The inferred amino acid sequences of 10 specific gene products from nine retroviruses were aligned by computer, all evolutionary distances between them calculated, and evolutionary trees constructed. Not unexpectedly, the various gene products are changing at different rates, the reverse transcriptase being the least and the envelope proteins the most different from one retrovirus to another. For the most part, trees based on the retroviral enzyme sequences are congruent, indicating that extensive genetic recombination has not been a major factor in the evolution of the central part of the genome. In the case of envelope protein sequences, however, the sequences clearly exhibit evidence of multiple cross-over events between quite distantly related retroviruses. A composite phylogenetic tree was constructed from the four retroviral enzyme sequences, and a number of important historical happenings were interpreted in the light of the time scale it affords.
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PMID:Sequence comparisons of retroviral proteins: relative rates of change and general phylogeny. 245 24


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