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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to evaluate tolerance, toxicity, and in vivo antigenicity, 29 HIV-1-infected patients (eight with ARC and 21 with AIDS) were vaccinated with a synthetic peptide derived from the gp41 transmembrane protein of the HIV-1. This peptide had been coupled with 2.4 dinitrophenyl-Ficoll (F46), a T-cell independent adjuvant. The patients received a single intradeltoid injection of either 0.1 or 0.3 mg of F46. Five of the individuals with AIDS were boostered, four of them twice. Anti-F46 antibody titers were measured before vaccination, and on days 7, 14, 21, 28, 90, 180 and 270 after vaccination. Anti-F46 titers rose at least twofold over prestudy values in 10/21 individuals with AIDS and in 1/8 individuals with ARC at least once during the observation period. The overall response, however, consisted of only weak antibody production that was independent of the dose or patient characteristics. No signs of toxicity or of clinical progression related to the vaccination were observed in this phase I/II trial of a T-cell independent therapeutic vaccine.
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PMID:Phase I/II vaccination study of recombinant peptide F46 corresponding to the HIV-1 transmembrane protein coupled with 2.4 dinitrophenyl (DNP) Ficoll. 791 56

To define the role of the human immunodeficiency virus type 1 (HIV-1) envelope proteins in virus infection, a series of peptides were synthesized based on various regions of the HIV-1 transmembrane protein gp41. One of these peptides, DP-178, corresponding to a region predictive of alpha-helical secondary structure (residues 643-678 of the HIV-1LAI isolate), has been identified as a potent antiviral agent. This peptide consistently blocked 100% of virus-mediated cell-cell fusion at < 5 ng/ml (IC90 approximately 1.5 ng/ml) and gave an approximately 10 times reduction in infectious titer of cell-free virus at approximately 80 ng/ml. The inhibitory activity was observed at peptide concentrations approximately 10(4) to 10(5) times lower than those at which cytotoxicity and cytostasis were detected. Peptide-mediated inhibition is HIV-1 specific in that approximately 10(2) to 10(3) times more peptide was required for inhibition of a human immunodeficiency virus type 2 isolate. Further experiments showed that DP-178 exhibited antiviral activity against both prototypic and primary HIV-1 isolates. As shown by PCR analysis of newly synthesized proviral DNA, DP-178 blocks an early step in the virus life cycle prior to reverse transcription. Finally, we discuss possible mechanisms by which DP-178 may exert its inhibitory activity.
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PMID:Peptides corresponding to a predictive alpha-helical domain of human immunodeficiency virus type 1 gp41 are potent inhibitors of virus infection. 793 89

Human immunodeficiency virus type 1 (HIV-1) has been shown to exhibit a specific basolateral release in polarized epithelial cells. Previous investigators have used vaccinia virus recombinants expressing HIV proteins to demonstrate that virus release is nonpolarized in the absence of viral envelope glycoproteins. In this study, we developed a transient expression system which allows the use of Madin-Darby canine kidney polarized epithelial cells directly grown on semipermeable membranes. This procedure allowed us to investigate polarized HIV viral budding following introduction of proviral DNA constructs. Expression of env gene products in trans demonstrated the ability to polarize env-negative viruses in a dose-dependent manner. The targeting signal for polarized virus release was shown to be present in the envelope gp41 transmembrane protein and absent from the gp120 portion of env. At least part of this signal is within the gp41 intracytoplasmic domain. Mutants of the p17gag matrix protein were shown to be nonpolarized only when unable to interact with the envelope glycoproteins. Together, these data are consistent with a model of polarized virus budding in which capsid proteins, lacking a targeting signal, are targeted for specific basolateral release via an interaction of p17 with the envelope glycoprotein containing the polarization signal in its intracytoplasmic domain.
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PMID:The intracytoplasmic domain of gp41 mediates polarized budding of human immunodeficiency virus type 1 in MDCK cells. 803 84

An antigen expressed by astrocytes in human brain tissue and by various human astrocytoma cell lines was shown to cross-react with a monoclonal antibody generated against amino acids (aa) 584 to 609 of the transmembrane protein gp41 of human immunodeficiency virus type 1 (HIV-1). This region is an immunodominant segment of gp41, and high levels of antibodies against this epitope have been detected in both serum and cerebrospinal fluid of HIV-infected individuals at all stages of HIV infection. Immunohistochemistry with this monoclonal antibody demonstrated the presence of a cross-reactive antigen in human brain tissue, with an increased frequency and intensity of staining in HIV-positive individuals when compared with HIV-negative controls. By using a panel of HIV-positive and -negative sera, we show that antibodies in HIV-positive serum specifically bound to the surfaces of human astrocytoma cells. HIV-positive sera depleted of antibodies recognizing gp41 aa 584 to 609 showed a significant diminution in cell surface binding. Conversely, the serum antibodies that bound to and were eluted from the aa 584 to 609 peptide also bound to the astrocyte cell surface. To identify the target antigen, the immunoreactivity of three astrocytoma cell lines was examined. By immunoprecipitation of metabolically labeled cell lysates and Western blot (immunoblot) analysis, we identified a protein of approximately 100 kDa as the target antigen. Cross-reactive antibodies between HIV proteins and astrocyte epitopes, such as this 100-kDa protein and others previously reported, suggests that an autoimmune response against these target antigens may disrupt the normal functions of astrocytes.
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PMID:Cross-reactivity of anti-human immunodeficiency virus type 1 gp41 antibodies with human astrocytes and astrocytoma cell lines. 808 66

Disseminated Mycobacterium avium infection in AIDS is associated with high tissue burdens (10(9)-10(10) mycobacteria/g tissue) of organism. The basis for the extraordinary susceptibility of AIDS to M. avium infection is unclear. HIV or its constituents may alter mononuclear phagocyte functions resulting in enhanced intracellular M. avium growth. The effects of an envelope glycoprotein (gp120), a transmembrane protein (p121), and core proteins of HIV-1 on M. avium infection of human monocytes were examined. Preculturing monocytes with gp120 inhibited M. avium phagocytosis and consistently enhanced intracellular growth of six M. avium strains. Pretreatment with p121, gag5, or p24 did not inhibit phagocytosis nor enhance intracellular growth of M. avium. Incubation of gp120 with soluble CD4 before addition to monocyte cultures or pretreatment of monocytes with OKT4A abrogated gp120 effects on M. avium phagocytosis and intracellular growth. gp120 also augmented cytokine production by infected monocytes. These results suggest that gp120, but not p121 or core proteins, modulate monocyte phagocytosis and enhance intracellular growth of M. avium at least in part through monocyte CD4 receptors. Direct effects of HIV-1 products may, therefore, contribute to the diathesis of AIDS to develop disseminated M. avium infection and to the extensive replication of the organisms within tissue macrophages.
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PMID:Modulation of the effector function of human monocytes for Mycobacterium avium by human immunodeficiency virus-1 envelope glycoprotein gp120. 811 20

Human immunodeficiency virus 1 (HIV-1) infection is associated with a vigorous cellular immune response that allows detection of cytotoxic T lymphocyte (CTL) activity using freshly isolated peripheral blood mononuclear cells (PBMC). Although restricting class I antigens and epitopes recognized by HIV-1-specific CTL have been defined, the effector cells mediating this vigorous response have been characterized less well. Specifically, no studies have addressed the breadth and duration of response to a defined epitope. In the present study, a longitudinal analysis of T cell receptor (TCR) gene usage by CTL clones was performed in a seropositive person using TCR gene sequences as a means of tracking responses to a well-defined epitope in the glycoprotein 41 transmembrane protein. 10 CTL clones specific for this human histocompatibility leukocyte antigen-B14-restricted epitope were isolated at multiple time points over a 31-mo period. All clones were derived from a single asymptomatic HIV-1-infected individual with a vigorous response to this epitope that was detectable using unstimulated PBMC. Polymerase chain reaction amplification using V alpha and V beta family-specific primers was performed on each clone, followed by DNA sequencing of the V-D-J regions. All 10 clones utilized V alpha 14 and V beta 4 genes. Sequence analysis of the TCR revealed the first nine clones isolated to also be identical at the nucleotide level. The TCR-alpha junctional region sequence of the tenth clone was identical to the junctional region sequences of the other nine, but this clone utilized distinct D beta and J beta gene segments. This study provides evidence that the observed high degree of HIV-1-specific CTL activity may be due to monoclonal or oligoclonal expansion of specific effector cells, and that progeny of a particular CTL clone may persist for prolonged periods in vivo in the presence of a chronic productive viral infection. The observed limited TCR diversity against an immunodominant epitope may limit recognition of virus variants with mutations in regions interacting with the TCR, thereby facilitating immune escape.
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PMID:Longitudinal analysis of T cell receptor (TCR) gene usage by human immunodeficiency virus 1 envelope-specific cytotoxic T lymphocyte clones reveals a limited TCR repertoire. 814 43

HIV, in contrast to animal retroviruses, is not lysed by human serum but nevertheless the virus as well as virus-infected cells activate the complement system efficiently. HIV activates the classical pathway by binding C1q to the transmembrane protein gp41. On the surface of HIV-infected cells, both the alternative and the classical pathway are activated. Complement-treated HIV has an enhanced ability to infect cells carrying receptors for C3 fragments. By this mechanism complement can target the virus to certain cells, e.g. follicular dendritic cells. HIV-infected complement-coated cells can interact with complement receptor carrying cells and thereby spread the infection or cause the destruction of the infected cells. Due to direct or indirect effects of HIV the complement system is in an activated state and the cellular expression of complement receptors as well as regulatory molecules is modified in the blood of HIV-infected patients.
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PMID:HIV and complement: role of the complement system in HIV infection. 829 98

A number of studies suggest a critical role of the HIV-1 envelope glycoprotein in cytopathogenesis, but the detailed mechanisms of cell injury remain to be defined. HIV-1 envelope proteins associate with the host cell membrane, and studies have demonstrated that HIV perturbs membrane structure and function. We describe here a structurally conserved region of the HIV-1 transmembrane protein (TM) that displays functional properties of target regions of proteins that interact directly with calcium-saturated calmodulin as part of cellular response cascades. The synthetic peptide homolog encompassing the carboxyl terminus (amino acid residues 828-855) of HIV-1 TM protein (LLP-1) is shown in standard in vitro assays to bind efficiently to purified calmodulin (CaM) and to inhibit in vitro CaM-mediated stimulation of phosphodiesterase activity. This suggests that this peptide homolog binds to CaM at affinities similar to those reported for a reference CaM-binding peptide. In addition, the CaM-dependent process of phospholipid synthesis can be inhibited in cell cultures by exogenous addition of the LLP-1. Finally, we have shown that the full-length TM protein binds CaM, whereas a truncated TM protein lacking the LLP-1 segment does not bind CaM. These results suggest a novel mechanism of viral cytopathogenesis mediated by the interaction of HIV-1 TM protein with cellular CaM, that could lead to an uncoupling of critical cellular signal transduction pathways.
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PMID:Identification of a calmodulin-binding and inhibitory peptide domain in the HIV-1 transmembrane glycoprotein. 831 49

An immune-selected point-mutation (HXB2-Env:Ala582(-->Thr)) in the transmembrane protein, gp41, of the human immunodeficiency virus type 1 confers relative insensitivity to neutralization by a number of sera from HIV-1-positive persons. Affinity-purified human antibodies to continuous epitopes spanning Ala582 do not neutralize the virus (C. Wilson, M. S. Reitz, Jr., K. Aldrich, P. J. Klasse, J. Blomberg, R. C. Gallo, and M. J. Robert-Guroff, J. Virol. 64, 3240-3248, 1990). The specificity of the antibodies that the mutation renders less active has not previously been determined. We now report that this substitution in gp41 reduces the neutralizing activity of monoclonal antibodies to discontinuous gp120 epitopes, which overlap with the CD4-binding site. There was no such difference in sensitivity to neutralization by soluble CD4, CD4-immunoglobulin, or by two monoclonal antibodies to the V3 region of gp120. Furthermore, the ability of 10 human HIV-1-positive sera to block the binding of soluble CD4 to mammalian-recombinant gp120 correlated weakly with their differentiation of neutralization between the wild-type and the Env:Ala582(-->Thr)-mutant virus. We thus suggest that the substitution in gp41 modulates the conformation of gp120 so as to decrease viral sensitivity to one category of antibodies which is partly responsible for the group-specific neutralization of HIV-1 by human sera.
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PMID:An immune-selected point mutation in the transmembrane protein of human immunodeficiency virus type 1 (HXB2-Env:Ala 582(-->Thr)) decreases viral neutralization by monoclonal antibodies to the CD4-binding site. 835 3

Previously we reported that synthetic peptide homologs of an amphipathic region (designated the lentivirus lytic peptide, or LLP-1) near the carboxy terminus of HIV-1 transmembrane protein (TM) were toxic for both prokaryotic and eukaryotic cells when added exogenously to cell cultures. We postulated that these peptides may exert their toxic effects in much the same manner as natural cytolytic peptides such as magainins, cecropins, and melittin by forming pores through cellular membranes. Here we show the results of 51Cr-release assays and membrane flux measurements of peptide treated cells that support our hypothesis. We have also tested a limited panel of LLP-1 peptide analogs in these assays and found that relatively minor alterations in peptide charge or amphipathicity in the parent HIV LLP-1 sequence resulted in total loss of membrane perturbative properties. These results demonstrate that the peptide homolog of HIV-1 LLP-1 can indeed perturb membranes by forming pores of defined size in cytoplasmic membranes. Furthermore, the analog studies described here reveal that the amphipathy and high positive charge of this protein segment are required for the membrane perturbative properties.
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PMID:Alterations in cell membrane permeability by the lentivirus lytic peptide (LLP-1) of HIV-1 transmembrane protein. 835 8


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