Extensive antigenic mimicry by retrovirus capsid proteins.
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Amino Acid Sequence↗
Biomedical subjects
R F Garry
Publications and source records attributed to R F Garry.
Characterization of a putative cellular receptor for HIV-1 transmembrane glycoprotein using synthetic peptides.
The transmembrane glycoprotein (gp41 or TM) of HIV-1 contains limited sequence similarity to TM of some immunosuppressive animal retroviruses. A specific HIV-1 TM sequence, denoted CS3, inhibits T-cell activation in vitro and antibody specific to CS3 has been linked to the absence of disease. CS3, when conjugated to human serum albumin (HSA) and labeled with fluorescein, binds specifically to CD4+ cell lines. Cross-linking of CS3-HSA to its binding activity on the CD4+ cell line RH9 reveals a putative subunit size of approximately 44 kD. Incubation of RH9 cells with CS3-HSA prior to addition of HIV-1 prevented HIV-1-mediated cell lysis and inhibited infection. These results suggest that the CS3 region of TM plays an important role in the pathogenesis of the AIDS virus, HIV-1.
Acquired Immunodeficiency Syndrome↗
A conserved idiotype and antibodies to retroviral proteins in systemic lupus erythematosus.
22 of 61 systemic lupus erythematosus (SLE) patients produced antibodies to the p24 gag protein of HIV-1 demonstrated by Western blotting. 20 of these 22 patients (91%) also express the 4B4 idiotype (Id 4B4) previously identified on a human anti-Sm monoclonal antibody called 4B4. This represents an enrichment for this Id (seen in only 52% of SLE patients generally). Eight of these 22 SLE patients also have anti-Sm antibody activity. Sm partially inhibits the antibody binding of p24 gag suggesting immunologic cross-reactivity between the retroviral antigen p24 gag and the autoantigen Sm. Anti-Id 4B4 also inhibits p24 gag antibody binding by as much as 40%. Finally the monoclonal antibody 4B4 showed cross-reactivity to Sm and p24 gag. The following points emerge from our studies: (a) SLE patients make antibodies to p24 gag of HIV-1, (b) there is a relationship between immunity to p24 gag and a conserved idiotype, and (c) anti-Sm antibodies can cross-react with p24 gag.
Autoantigens↗
The role of monovalent cation transport in Sindbis virus maturation and release.
Alterations in intracellular monovalent cation concentrations in Sindbis virus-infected avian cells result, in part, from a reduction in Na+/K+ ATPase (Na+ pump) activity. Inhibition of Na+ pump activity was shown previously to temporally correlate with the appearance of viral envelope proteins on the cell surface and the release of virus particles. Cells infected with envelope-defective temperature-sensitive mutants exhibited reduced Na+ pump activity at the nonpermissive temperature, where viral particles are not released. By contrast, Na+ pump activity was not inhibited in Sindbis virus-infected cells treated with tunicamycin or with antiviral serum, which block virus maturation and release. Diuretic-sensitive transport of 86Rb+, aK+ tracer, was stimulated in cells which express virus envelope proteins, but fail to release virus particles. In these cells, the furosemide-sensitive 86Rb+ influx exhibited an increase in Vmax and was responsive to changes in the extracellular concentration of NaCl. Furosemide inhibited the rapid release of virus from low salt-inhibited cells after shift to isotonic conditions. Alterations in ion transport during alphavirus infection may, therefore, facilitate the efficient release of progeny virus particles.
Biological Transport↗
Alteration of intracellular monovalent cation concentrations by a poliovirus mutant which encodes a defective 2A protease.
Poliovirus mutant 2A-1, which encodes a defective protease 2A, fails to inhibit translation of capped mRNAs selectively. Despite the failure of 2A-1 to inactivate cap-dependent translation, a reduction in the overall rate of protein synthesis, both virus and cell-specified, does occur after 2A-1 infection. This global reduction in protein synthesis is temporally correlated with an increase in [Na+]i and a decrease in [K+]i. The extensive global shutoff of protein synthesis is not observed in 2A-1 infected cells incubated in low NaCl medium or medium containing an elevated concentration of KCl which compensate for the virally-induced alterations in intracellular monovalent cation concentrations. Furthermore, 2A-1-specified protein synthesis is only partly resistant to hypertonic NaCl media which increase [Na+]i, in contrast to protein synthesis specified by wild-type poliovirus. These results suggest that shutoff of host and viral protein synthesis during infection by poliovirus mutant 2A-1 is a consequence of the virus-induced changes in intracellular monovalent cation concentrations.
Mutation↗
A general model for the transmembrane proteins of HIV and other retroviruses.
A hypothetical model of the transmembrane (TM) protein of human immunodeficiency virus (HIV) is proposed that is derived from the known structure of the influenza TM protein HA2. This model is consistent with computer algorithms of predicted protein structure and with known properties of TM proteins determined by sequence homology, site-directed mutations, peptide analogs, immunochemistry, or other biologic means. It is applicable to a wide variety of retroviral TM proteins differing widely in overall molecular weight.
Algorithms↗
Potential mechanisms for the cytopathic properties of HIV.
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Acquired Immunodeficiency Syndrome↗
Documentation of an AIDS virus infection in the United States in 1968.
The acquired immunodeficiency syndrome was first recognized as a clinical entity in the United States in the early 1980s; however, the issue of when human immunodeficiency virus, the causative agent of the acquired immunodeficiency syndrome, was introduced into at-risk populations in the United States is unresolved. Previously, we reported the case study of a 15-year-old black male who was admitted to St Louis City Hospital in 1968 for extensive lymphedema of the genitalia and lower extremities. Chlamydial organisms were widely disseminated and isolated from numerous body fluids and organs. Over a 16-month clinical course his condition progressively deteriorated, and at autopsy there was widespread Kaposi's sarcoma of the aggressive, disseminated type. Recently performed Western blot and antigen capture assays on serum and autopsy tissue specimens frozen since 1969 have disclosed that this sexually active teenager was infected with a virus closely related or identical to human immunodeficiency virus type 1. The clinical and immunologic findings together suggest that an immunosuppressive retrovirus existed in the United States before the late 1970s.
Acquired Immunodeficiency Syndrome↗
Autogenous growth factor production by reticuloendotheliosis virus-transformed hematopoietic cells.
Reticuloendotheliosis virus strain T (REV-T)-transformed cells gave rise spontaneously to variants which secrete a factor that forms a distinct visible ring of precipitation (halo) surrounding colonies grown in soft agar. An Mr 15,000 protein was produced at higher levels by halo variants than by nonhalo-producing cells. An assay designed to detect the formation of precipitates enabled purification of an Mr 15,000 protein, p15, from serum-free medium conditioned by the growth of REV-T-transformed hematopoietic cells. Fractions enriched in p15 permitted the growth of REV-T-transformed cells under conditions where they normally failed to proliferate.
Animals↗
Cell surface effects of human immunodeficiency virus.
Cell killing by human immunodeficiency virus (HIV) is thought to contribute to many of the defects of the acquired immunodeficiency syndrome (AIDS). Two types of cytopathology are observed in HIV-infected cultured cells: cell-cell fusion and killing of single cells. Both killing processes appear to involve cell surface effects of HIV. A model is proposed for the HIV-mediated cell surface processes which could result in cell-cell fusion and single cell killing. The purpose of this model is to define the potential roles of individual viral envelope and cell surface molecules in cell killing processes and to identify alternative routes to the establishment of persistently-infected cells. Elucidation of HIV-induced cell surface effects may provide the basis for a rational approach to the design of antiviral agents which are selective for HIV-infected cells.
Biological Transport, Active↗
Poliovirus protease 2A is required for interference with vesicular stomatitis virus-specified protein synthesis.
A subunit of eukaryotic initiation factor-4F (eIF-4F) which is a component of the protein complex which binds to the methylated cap structure at the 5' end of most cellular mRNAs, is proteolytically cleaved in poliovirus-infected cells resulting in the shutoff of cellular protein synthesis. Poliovirus mRNA is selectively translated in infected cells, in part, because translation of the uncapped viral mRNA does not require an intact cap binding protein complex. Wild-type poliovirus also inhibits the translation of vesicular stomatitis virus (VSV) mRNAs in coinfected cells, however, it has been unclear whether similar mechanisms are employed by poliovirus to interfere with cellular and VSV protein synthesis. Degradation of eIF-4F appears to be an indirect function of the poliovirus-encoded protease 2A. A poliovirus mutant in 2A failed to mediate eIF-4F cleavage and selectively terminate translation of capped cellular mRNAs. Unlike wild-type poliovirus, 2A-1 does not interfere with VSV-specified protein synthesis. These results indicate that the same viral protein, 2A protease, is required not only to effectively terminate host protein synthesis, but also to interfere with expression of a heterologous virus, VSV. In addition, 2A-1 specifies a function, heretofore undescribed for poliovirus, which interferes with VSV-induced shutoff of protein synthesis.
Animals↗
Sindbis virus infection decreases intracellular pH: alkaline medium inhibits processing of Sindbis virus polyproteins.
Infection of baby hamster kidney cells by Sindbis virus, an alphavirus, resulted in a decrease in the intracellular pH of approximately 0.5 units within the first 1-2 hr after infection as measured either by equilibrium labeling with [14C]benzoic acid or by use of a pH-sensitive fluorescent probe, 2,7-bis-carboxyethyl-5,6-carboxyfluorescein-acetooxymethyl ester. In contrast, intralysosomal pH, as measured using an endocytized pH-sensitive probe, fluorescein isothiocyanate-labeled dextran, was not altered by Sindbis virus infection. Production of Sindbis virus was reduced by more than 90% and post-translational processing of Sindbis virus envelope precursors was inhibited in infected cells incubated in alkaline medium.
Animals↗
Development of immunosupportive drugs for patients with AIDS/ARC.
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AIDS-Related Complex↗
Induction of the stress response: alterations in membrane-associated transport systems and protein modification in heat shocked or Sindbis virus-infected cells.
Heat shock or Sindbis virus infection of chick embryo (CE) or baby hamster kidney (BHK) cells resulted in a decrease in the uptake of 86Rubidium+, a K+ tracer. Both stressful treatments decreased 86Rb+ uptake by inhibition of the ouabain-sensitive Na+/K+ ATPase. Alterations in the intracellular levels of monovalent ions may be involved in translational or transcriptional control of the stress response. Heat shock or Sindbis virus infection also resulted in an increase in rate of uptake of [3H]deoxy-D-glucose and a decrease in the incorporation of [3H]glucosamine or [3H]mannose into most cellular proteins. These results suggested that heat shock or Sindbis virus infection alter hexose metabolism and that abnormally glycosylated proteins may accumulate in stressed cells. Exposure of uninfected chick embryo cells to elevated temperature had little effect on the overall rate of incorporation of [32P]orthophosphate into cellular proteins. However, one protein (Mr 31,000; pp31) displayed increased incorporation of [32P]orthophosphate and two other proteins (Mr 33,000 and 20,000; pp33 and pp20) displayed decreased incorporation. Sindbis virus infection failed to mimic or to modify these heat shock induced alterations in protein phosphorylation.
Animals↗
Cell killing by ultraviolet-inactivated human immunodeficiency virus.
Extensive cell killing and cytopathology were observed within 24 hr after exposure of a clonal cell line of human T-4 lymphocytes (RH9) to culture supernatants containing human immunodeficiency virus (HIV). Ultraviolet-irradiated HIV-containing culture fluids were also capable of killing RH9 cells and of inducing specific cytopathic effects which were indistinguishable from those induced by unirradiated virus-containing preparations. The uv-irradiated HIV was incapable of forming proviral DNA using the endogenous virion genomic RNA as a template. The RH9 cells persistently infected with HIV did not release soluble cytotoxic factors to account for the cell killing observed when culture supernatants were added to uninfected RH9 cells. The fraction involved in cell killing had the hydrodynamic properties of a retrovirus. These results suggest that a virion component is responsible for cell killing by HIV.
Cell Line↗
Intracellular K+ and the expression of transformation parameters by chick cells transformed with the Bryan strain of Rous sarcoma virus.
As normal chick embryo (CE) cells entered quiescence the intracellular concentrations of both Na+ and K+ declined. Comparable decreases in intracellular concentrations of Na+ and K+ were not observed in CE cells transformed by either the Schmidt-Ruppin (SR) or the Bryan (B) strain of Rous sarcoma virus (RSV). Intracellular concentrations of Na+ were higher in SR-RSV-transformed CE cells than in B-RSV-transformed cells and uninfected CE cells at all times after plating. In contrast, intracellular concentrations of K+ were higher in B-RSV-transformed CE cells than in SR-RSV-transformed cells. Uninfected CE cells incubated in medium containing an elevated concentration of K+ (an increase from 5 to 30 mM) exhibited several, but not all, of the transformation parameters expressed by B-RSV-transformed CE cells.
Animals↗
Sindbis virus infection increases hexose transport in quiescent cells.
Sindbis virus infection of baby hamster kidney cells or chick embryo cells resulted in a significant increase in the rate of uptake of [2-3H]deoxy-D-glucose ([3H]dGlu). Stimulation of hexose transport in Sindbis virus-infected cells occurred only if the cells were rendered quiescent by culturing at high density or by serum starvation. In contrast, Sindbis virus-induced inhibition of potassium transport, measured as a decrease in the uptake of 86Rb+, was independent of cell growth state. Stimulation of [3H]dGlu uptake in Sindbis virus-infected cells was the result of an increase in the Vmax of the hexose transporter, but not a change in the Km. The stimulation of [3H]dGlu uptake induced by Sindbis virus was insensitive to the drug actinomycin D, but was blocked by cordycepin. The stimulation was also insensitive to treatment with tunicamycin, which prevented the virally induced inhibition of the plasma membrane-associated Na+/K+ ATPase and termination of host protein synthesis.
Animals↗
The ratio of plasma membrane cholesterol to phospholipid and the inhibition of Sindbis virus maturation by low NaCl medium.
Sindbis virus maturation is inhibited by low NaCl medium in chick embryo cells and in one strain of BHK cells, but not in another strain of BHK cells which has a different passage history. The plasma membrane of the cells in which Sindbis virus maturation is resistant to low NaCl medium has a higher ratio of cholesterol to phospholipid than the other cells. Cholesterol-containing liposomes, but not cholesterol-free liposomes, can release Sindbis virus from low NaCl-inhibited cells. These results suggest that low NaCl medium may block Sindbis virus maturation by a mechanism which is influenced by the ratio of plasma membrane cholesterol to phospholipid.
Animals↗