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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Natural selection on polymorphic protein-coding loci of human immunodeficiency virus-1 (HIV-1), the more geographically widespread of the two viruses causing human acquired immune deficiency syndrome (AIDS), was studied by estimating the rates of nucleotide substitution per site in comparisons among alleles classified in families of related alleles on the basis of a phylogenetic analysis. In the case of gag, pol, and gp41, the rate of synonymous substitution generally exceeded that of nonsynonymous substitution, indicating that these genes are subject to purifying selection. However, in the case of several of the variable (V) regions of the gp120 gene, especially V2 and V3, comparisons within and between families often showed a significantly higher rate of nonsynonymous than of synonymous nucleotide substitution. This pattern of nucleotide substitution indicates that positive Darwinian selection has acted to diversify these regions at the amino acid level. The V regions have been identified as probable epitopes for antibody recognition; therefore, avoidance of such recognition seems likely to be the basis for positive selection on these regions. By contrast, regions of HIV-1 proteins identified as epitopes for T cell recognition show no evidence of positive selection and are often highly conserved at the amino acid level. These results suggest that selection favoring avoidance of T cell recognition has not been a major factor in the history of HIV-1 and thus that avoidance of T cell recognition is not likely to be a major factor in the pathogenesis of AIDS.
Mol Biol Evol 1995 Sep
PMID:Natural selection on the gag, pol, and env genes of human immunodeficiency virus 1 (HIV-1). 747 26

Human immunodeficiency virus types 1 and 2 (HIV-1, -2), the etiological agents of AIDS, are retroviruses that replicate in CD4+ T lymphocytes, monocytes, and macrophages. Early anti-HIV therapies were directed at the step in the virus life cycle that was considered the most readily blocked: the transcription of viral RNA into its DNA copy by the viral enzyme reverse transcriptase (RT). Unfortunately, to date, patient therapies have been relatively unsuccessful and hampered by toxicological problems. This has promoted further research into inhibitors of HIV replication, which may act at alternative stages in the viral replicative cycle as well as more effective RT inhibitors. In order to facilitate such research, simple and accurate in vitro assays are highly desirable. Here we describe such assays that measure components of the HIV replicative cycle and are suitable for use within antiviral experiments.
Mol Biotechnol 1994 Feb
PMID:In vitro assessment of compounds for anti-HIV activity. 753

Progression to AIDS and death were evaluated in 112 patients, 84 with hemophilia A and 28 with hemophilia B. Seroconversion period and age at seroconversion were similar in both groups. 36/112 patients died: 21/84 with hemophilia A (25%) and 15/28 (54%) with hemophilia B. Mean survival time was 11.7 years. The 10-year cumulative survival was 75.8%. It was lower in hemophilia B (56.2%) compared to hemophilia A patients (82.4%; p = 0.002). 37 patients (33%) developed full-blown AIDS: 26 with hemophilia A (31%) and 11 with hemophilia B (39%). Mean AIDS-free survival time was 11.4 years. The 10-year cumulative AIDS-free survival was 71.2%. It was 74.8% in hemophilia A and 60.3% in hemophilia B patients. CD4 counts lower than 200/cmm occurred in 62 patients (56%): 45 with hemophilia A (54%) and 17 with hemophilia B (63%). The mean time to CD4 counts lower than 200 was 9.4 years. Mean survival time in older seroconverters (35 year old or more) was shorter than in younger (9.5 vs. 11.7 years, p < 0.05). Mean CD4 cell counts at seroconversion were similar in hemophilia A and B patients and in different age classes at seroconversion. CD4 cell counts at seroconversion affected the survival: 90% seroconverters with CD4 cell counts of 800/cmm or more were alive at 10 years vs. 60% of seroconverters with CD4 cell counts lower than 800 (p < 0.05).
Cell Mol Biol (Noisy-le-grand) 1995 May
PMID:Factors associated with progression to AIDS and mortality in a cohort of HIV-infected patients with hemophilia followed up since seroconversion. 758 Aug 30

A randomized, placebo-controlled trial was designed to evaluate safety and immunogenicity of an anti-cytokine vaccine in high risk HIV-positive patients. This strategy was aimed to modulate the impaired cytokine regulation in AIDS. Twelve asymptomatic patients on antiretroviral therapy for at least 1 year and with CD4 cell counts between 100-300/mm3 were randomized to receive adjuvanted formol-inactivated interferon alpha-2a (IFN alpha) and continue the current antiretroviral treatment, whatever it was, or to receive the adjuvant alone and the current antiretroviral treatment. All patients received 4 i.m. injections monthly, followed by booster injections every 3 months. Clinical status, immunology and virology were monitored. Immune response to vaccination was evaluated in term of antibody detection (ELISA) and serum anti-IFN alpha neutralizing capacity. Only local discomfort and transient fever were reported. All vaccines except one showed increased levels of anti-IFN alpha Abs and developed serum IFN alpha neutralizing capacity. Viral load did not increase in vaccinees while it remained unchanged or even increased in placebo-treated patients. None of them showed HIV-related symptoms and all had their CD4 cell counts stabilized over 18 months, whereas 2 placebo-treated patients developed full-blow AIDS. In conclusion, anti-IFN alpha vaccine was safe and immunogenic. Stable clinical and immunological status over 18 months was observed in vaccinees coupled to increased serum IFN alpha neutralizing capacity.
Cell Mol Biol (Noisy-le-grand) 1995 May
PMID:Anti-alpha interferon immunization: safety and immunogenicity in asymptomatic HIV positive patients at high risk of disease progression. 758 Aug 31

The natural and medical sciences have strongly benefitted from technological advances that help to create and store more raw information than can be effectively processed. In particular, this rapid growth has created a strong need for a flexible and far-reaching approach to cross-database simulation. The paper uses a highly simplified example, called the 'TinyMouse' simulator, to explain the design and functioning of interactive cross-database simulators that can be applied to prototype experiments with animal models of human disease, such as the hu-SCID mouse model for the Acquired Immune Deficiency Syndrome (AIDS). Work in progress is discussed to extend 'TinyMouse' into 'CyberMouse', an informational organism that synthesizes factual databases of the murine neuroendocrine-immune system.
Proc Int Conf Intell Syst Mol Biol 1993
PMID:Testing HIV molecular biology in in silico physiologies. 758 57

A major obstacle to understanding AIDS is the lack of a suitable small animal model for studying HIV-1 infection and the subsequent development of AIDS, and for testing diagnostic, therapeutic, and preventive modalities. Our goal is to produce a rabbit model for the study of AIDS. Here we report on the generation of transgenic rabbits that express the human CD4 (hCD4) gene. The transgene, which contains the coding region for hCD4 and approximately 23 kb of sequence upstream of the translation start site, was used previously to direct hcD4 expression on the surface of CD4+ T cells of transgenic mice (Gillespie et al., 1993: Mol Cell Biol 13:2952-2958). The hCD4 transgene was detected in five males and two females derived from the microinjection in five males and two females derived from the microinjection of 271 rabbit embryos. Both hCD4 RNA and protein were expressed in peripheral blood lymphocytes (PBLs) from all five males but neither of the females. Human CD4 was expressed on PBLs from F1 offspring of all founder males. T-cell subset analysis revealed that hCD4 expression was restricted to rabbit CD4 (rCD4) expressing lymphocytes; mature rCD4- rCD8+ lymphocytes did not express hCD4. In preliminary studies, PBLs from hCD4 transgenic rabbits produced greater amounts of HIV-1 p24 core protein following HIV-1 infection in vitro than HIV-1 p24 antigen in nontransgenic rabbit infected cultures. These results extend to rabbits our previous observation that this transgene contains the sequence elements required for high-level expression in the appropriate cells of transgenic mice. Furthermore, these and previous studies demonstrating that expression of hCD4 protein enhances HIV-1 infection of rabbit T cells in vitro, coupled with reports that normal, nontransgenic rabbits are susceptible to HIV-1 infection, suggests that the hCD4 transgenic rabbits described herein will have an increased susceptibility to HIV-1 infection. In vivo HIV-1 infection studies with these rabbits are under way.
Mol Reprod Dev 1995 Apr
PMID:Developmental and tissue-specific expression of human CD4 in transgenic rabbits. 759 7

Gelonin is a single chain ribosome inactivating protein (RIP) with potential application in the treatment of cancer and AIDS. Diffraction quality crystals grown using PEG3350, belong to the space group P21, with a = 49.4 A, b = 44.9 A, c = 137.4 A and beta = 98.4 degrees, and contain two molecules in the asymmetric unit. Diffraction data collected to 1.8 A resolution has a Rm value of 7.3%. Structure of gelonin has been solved by the molecular replacement method, using ricin A chain as the search model. Crystallographic refinement using X-PLOR resulted in a model for which the r.m.s deviations from ideal bond lengths and bond angles are 0.012 A and 2.7 degrees, respectively. The final R-factor is 18.4% for 39,806 reflections for which I > 1.0 sigma (I). The C alpha atoms of the two molecules in the asymmetric unit superpose to within 0.38 A for 247 atom pairs. The overall fold of gelonin is similar to that of other RIPs such as ricin A chain and alpha-momorcharin, the r.m.s.d. for C alpha superpositions being 1.3 and 1.4 A, respectively. The catalytic residues (Glu166, Arg169 and Tyr113) in the active site form a hydrogen bond scheme similar to that observed in other RIPs. The conformation of Tyr74 in the active site, however, is significantly different from that in alpha-momorcharin. Three well defined water molecules are located in the active site cavity, and one of them, X319, superposes to within 0.2 A of a corresponding water molecule in the structure of alpha-momorcharin. Any of the three could be the substrate water molecule in the hydrolysis reaction catalysed by gelonin. Difference electron density for a N-linked sugar moiety has been observed near only one of the two potential glycosylation sites in the sequence. The amino acid at position 239 has been established as Lys by calculation of omit electron density maps. The two cysteine residues in the sequence, Cys44 and Cys50, form a disulphide bond, and are therefore not available for disulphide conjugation with antibodies. Based on the structure, the region of the molecule that is involved in intradimer interactions is suggested to be suitable for introducing a Cys residue for purposes of conjugation with an antibody to produce useful immunotoxins.
J Mol Biol 1995 Jul 14
PMID:X-ray structure of gelonin at 1.8 A resolution. 760 81

Recombinant proteins have been proposed as subunit vaccines for many viral, bacterial and parasitic diseases, to reduce adverse side effects associated with inactivated or attenuated vaccines. Yet little is known about the comparative immunogenicity of recombinant proteins vs native forms present in cells or on organisms, and little is known about comparisons of the specificities of such immune responses. In another observation about differing forms of an antigen, about 10% of AIDS patients have anti-CD4 autoantibodies recognizing sites seen in recombinant CD4 (rCD4) but not present on cell surface CD4. We have analyzed antibody responses of mice to human CD4 when presented in recombinant or in cellular form. The response to the whole molecule was examined, as well as the responses to two sites within the molecule. In addition, any effect of immune response genes in the responding animal was sought, which might potentially restrict or modify any response to CD4. Mice immunized with rCD4 generated a large response to rCD4, but a lower response to the cell surface form, implying that additional sites are recognized on the recombinant form that are not recognized in the cellular form. Mice immunized with cells containing surface CD4 had high titers of antibody reactive with whole cells, of which only a small portion was reactive with rCD4. Titers on rCD4 are much lower for these mice than in rCD4-immunized mice. Both forms of CD4 induced antibodies to the gp120 binding site with comparable efficiency. For another site in domain 3 or 4 of CD4, cellular CD4 induced antibodies more frequently than the recombinant form. Immune response gene differences did not play a detectable role in the anti-CD4 response.
Mol Immunol 1993 Jun
PMID:Recombinant human CD4 elicits antibody responses different in epitope specificity from those that cellular CD4 elicits. 768 21

In the search for 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives, we have found 6-benzyl-1-(ethoxymethyl)-5-isopropyl-uracil (MKC-442) to be a highly potent and selective inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). The IC50 value of MKC-442 for HIV-1 RT was 8 nM. MKC-442 did not inhibit HIV-1 RNase H, other RTs, or DNA polymerase alpha. Because its inhibitory pattern showed noncompetitive inhibition with regard to nucleotide substrates, its mode of action was considered to be allosteric inhibition. From the results of combination studies, MKC-442 was found to produce synergistic inhibition of HIV-1 RT with 3'-azido-2',3'-dideoxythymidine (AZT) 5'-triphosphate (AZT.TP). The dose of AZT.TP required for 50% inhibition was reduced to one tenth of control in the presence of a half dose of MKC-442. Although other allosteric inhibitors (Nevirapine, L-696,229, and R82,913) had the same specificity for enzyme inhibition, they did not show synergism with AZT.TP in the combination index and synergy plot analyses. Synergistic inhibition of HIV-1 replication by MKC-442 and AZT has also been observed in HIV-1-infected MT-4 cells. These results suggest that MKC-442 is a unique inhibitor of HIV-1 RT, and combination therapy with MKC-442 and AZT could be advantageous in the treatment of acquired immune deficiency syndrome.
Mol Pharmacol 1993 Oct
PMID:Selective and synergistic inhibition of human immunodeficiency virus type 1 reverse transcriptase by a non-nucleoside inhibitor, MKC-442. 769 70

Laboratory diagnosis of mycoplasma infections is hampered by the difficulty or total failure to cultivate the organisms in vitro, and by the frequently weak and poorly specific serological response of the host. DNA probes consisting of cloned ribosomal RNA genes, cDNA to mycoplasmal rRNA, synthetic 16S rRNA oligonucleotide sequences, or cloned mycoplasmal protein genes, have been developed and applied as diagnostic tools in a variety of human and animal mycoplasma infections. These included primary atypical pneumonia caused by Mycoplasma pneumoniae, urogenital infections associated with M. genitalium and Ureaplasma urealyticum, and infections with M. fermentans, M. penetrans or M. pirum--mycoplasmas recently incriminated as cofactors in AIDS. DNA probes were also designed to aid in diagnosis of mycoplasma diseases of farm and laboratory animals, and the hard-to-diagnose mycoplasma infections of cell cultures. Sensitivity of mycoplasma detection by the different probes ranged between 10(3) and 10(6) colony-forming units, a level which may not be sufficiently high for use in a clinical laboratory. The introduction of PCR has pushed aside the previously developed DNA probes, by providing faster and much more sensitive tests. The sensitive level of a PCR test can be as low as a single organism, enabling detection of mycoplasmas in patients treated with antibiotics and in asymptomatic patients. PCR becomes positive prior to serological response and is also effective in immunocompromised hosts. PCR was shown to be most valuable in detection and identification of the non-culturable plant and insect mycoplasma-like organisms (MLOs). Nevertheless, false-negative PCR results are rather common due to inhibitors of the PCR reaction in the clinical specimen, while false-positive results may occur due to contamination of the reagents with target DNA. In conclusion, the PCR procedure is still too complex to be carried out in a routine diagnostic laboratory. PCR prepackaged quality-controlled diagnostic kits are now in the process of rapid development. Once these kits become available, and at a reasonable cost, PCR will certainly take its place as a major diagnostic tool in the routine diagnosis of mycoplasma infections.
Mol Cell Probes 1994 Dec
PMID:DNA probes and PCR in diagnosis of mycoplasma infections. 770 Feb 72


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