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)

Cationic polymers are known to have potent activity against bacteria, but their effects on viral activity have been little studied. We investigated the effect of one such polymer, polyethyleneimine (PEI), on HIV-1 infection. Although virus-cell binding was significantly inhibited by PEI, HIV-1 infection in human T-cell lines such as MT-4 and MOLT-4 was accelerated conversely when the drug treatment was carried out, after the virus had attached to the cells or PEI was simultaneously added to the virus and cell culture system. This paradoxical effect of PEI on HIV-1 infection was examined using HIV-1 chronically infected cells (MOLT-4/HIV-1). Dissociation of the glycoprotein gp120 (as revealed by exposure of transmembrane protein gp41) from MOLT-4/HIV-1 cells and the resultant fusion of these cells was shown to be induced by the addition of PEI. Accordingly, it was suggested that the binding inhibition of HIV-1 to CD4-positive cells by PEI was due to the shedding of gp120 from HIV-1 particles, and this PEI rather promoted membrane fusion between the virus and cells leading to the enhancement of HIV-1 infection. Similarly, dissociation of gp120 from MOLT-4/HIV-1 was also induced by sCD4. The effect of these reagents on changes in membrane fluidity was evaluated by polarization (p) measurements, and it was observed that the acceleration of membrane fluidity occurred only in the PEI system. Therefore, it is likely that PEI accelerates HIV-1 infection by facilitating virus entry into the host cells through an increase in membrane fluidity.
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PMID:Enhancement of human immunodeficiency virus type 1 (HIV-1) infection via increased membrane fluidity by a cationic polymer. 957 41

HIV-1 uses CD4 and chemokine receptors as cofactors for cellular entry. The viral envelope transmembrane protein gp41 is thought to participate in viral fusion with CD4(+) cells. We investigated whether gp41 interacts with chemokine receptors on human monocytes by testing its effect on the capacity of cells to respond to chemokine stimulation. Monocytes preincubated with gp41 of the MN strain showed markedly reduced binding, calcium mobilization, and chemotaxis in response to a variety of chemokines as well as to the bacterial peptide fMLP. This generalized inhibition of monocyte activation by chemoattractants required the presence of CD4, since the effect of gp41 was only observed in CD4(+) monocytes and in HEK293 cells cotransfected with chemokine receptors and an intact CD4, but not a CD4 lacking its cytoplasmic domain. Confocal microscopy showed that gp41 caused internalization of CXCR4 in HEK293 cells provided they were also cotransfected with intact CD4. In addition, pretreatment of monocytes with protein kinase C inhibitors partially reversed the inhibitory effect of gp41. Thus, gp41, which had not previously been implicated as interacting with HIV-1 fusion cofactors, downregulates chemoattractant receptors on monocytes by a CD4-dependent pathway.
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PMID:HIV-1 envelope gp41 is a potent inhibitor of chemoattractant receptor expression and function in monocytes. 971 Apr 49

The transmembrane protein of HIV-1, gp41, mediates fusion between membranes of the virus and target cell. Strong interaction between the helical regions in the ectodomain of gp41 has been exploited to develop a method that can detect a potential inhibitor against gp41. The N-terminus coiled-coil or the C-terminus helical sequences within the ectodomain of gp41 were inserted into the C-terminus of thioredoxin (Trx) or glutathione S-transferase (GST) to generate the fusion proteins, Trx-N and GST-C, respectively. The inserted sequences of GST-C and Trx-N cause the two proteins to interact with each other and to form a complex. Furthermore, GST-C binds specifically to the surface-coated Trx-N, and the amount of attached GST-C is detected by an ELISA assay using anti-GST antibodies. Peptides derived from the helical regions of gp41 compete with GST-C for binding to Trx-N as well as prevent the gp41-mediated cell fusion. This in vitro assay system can be applied to screening compounds that have an inhibitory activity against gp41.
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PMID:Development of an in vitro assay system for screening of gp41 inhibitory compounds. 989 25

A recombinant vaccinia virus (rvv) expressing, human immunodeficiency virus type 1 (HIV-1) external envelope glycoprotein, gp120, fused to a non-cleavable transmembrane protein, vvE13, elicited protection against a tumor cell line expressing HIV-1 full length envelope glycoprotein, gp160, in mice. Mice vaccinated with vvE13 exhibited a decreased incidence of tumor development and significantly smaller tumors in comparison to mice vaccinated with rvv gp160, vvE1, or a thymidine kinase minus (TK-) rvv, vSC11, or phosphate-buffered saline (PBS) injected controls. vvE13 and vvE1 also delayed tumor development, compared to vSC11 and PBS-injected controls; however, a statistical correlation could not be demonstrated due to the development of tumors in so few animals. Specificity toward HIV-1 envelope glycoprotein, was shown, since HIV-1 envelope-tumor prevention (incidence for vvE13 and size for vvE1 and vvE13 and delay for vvE1 and vvE13) was statistically superior with HIV-1 envelope expressing tumors compared to parenteral tumors. The vvE13 recombinant vaccinia virus expressing the HIV-1 envelope glycoprotein gp120 fused to a non-cleavable transmembrane protein elicits superior protection against tumors expressing the gp160 envelope glycoprotein, as compared to vvE1 expressing gp160.
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PMID:Enhanced HIV-1 envelope-tumor protection by a recombinant vaccinia virus expressing anchored HIV-1 gp120 lacking gp41. 1008 12

Retroviral entry into cells depends on envelope glycoproteins, whereby receptor binding to the surface-exposed subunit triggers membrane fusion by the transmembrane protein (TM) subunit. We determined the crystal structure at 2.5-A resolution of the ectodomain of gp21, the TM from human T cell leukemia virus type 1. The gp21 fragment was crystallized as a maltose-binding protein chimera, and the maltose-binding protein domain was used to solve the initial phases by the method of molecular replacement. The structure of gp21 comprises an N-terminal trimeric coiled coil, an adjacent disulfide-bonded loop that stabilizes a chain reversal, and a C-terminal sequence structurally distinct from HIV type 1/simian immunodeficiency virus gp41 that packs against the coil in an extended antiparallel fashion. Comparison of the gp21 structure with the structures of other retroviral TMs contrasts the conserved nature of the coiled coil-forming region and adjacent disulfide-bonded loop with the variable nature of the C-terminal ectodomain segment. The structure points to these features having evolved to enable the dual roles of retroviral TMs: conserved fusion function and an ability to anchor diverse surface-exposed subunit structures to the virion envelope and infected cell surface. The structure of gp21 implies that the N-terminal fusion peptide is in close proximity to the C-terminal transmembrane domain and likely represents a postfusion conformation.
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PMID:Crystal structure of human T cell leukemia virus type 1 gp21 ectodomain crystallized as a maltose-binding protein chimera reveals structural evolution of retroviral transmembrane proteins. 1020 Feb 60

The high degree of genetic diversity within human immunodeficiency virus type 1 (HIV-1), which includes two major groups, M (major) and O (outlier), and various env subtypes within group M (subtypes A to J), has made designing assays that will detect all known HIV-1 strains difficult. We have developed a generic primer set based on the conserved immunodominant region of transmembrane protein gp41 that can reliably amplify as few as 10 copies/PCR of viral DNA from near-full-length clones representing group M subtypes A to H (subtypes I and J were not available). The assay is highly sensitive in detecting plasma viral RNA from HIV-1 strains of diverse geographic origins representing different subtypes of HIV-1 group M as well as HIV-1 group O. Of the 253 group M plasma specimens (subtypes A, 68 specimens; B, 71; C, 19; D, 27; E, 23; F, 33; and G, 12), 250 (98.8%) were amplified by using the gp41 M/O primer set. More importantly, all 32 (100%) group O plasma samples were also amplified with these primers. In vitro spiking experiments further revealed that the assay could reliably detect as few as 25 copies/ml of viral RNA and gave positive signals in HIV-1-seropositive specimens with plasma copy numbers below the limits of detection by all commercially available viral load assays. In addition, analysis of five seroconversion panels indicated that the assay is highly sensitive for early detection of plasma viremia during the "window period." Thus, the highly sensitive assay will be useful for early detection of HIV-1 in clinical specimens from all known HIV-1 infections, regardless of their genotypes and geographic origins.
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PMID:Detection of phylogenetically diverse human immunodeficiency virus type 1 groups M and O from plasma by using highly sensitive and specific generic primers. 1040 5

The heat-shock protein hsp60 is typically found in mitochondria, but, in smaller amounts, also in the cell cytoplasm and associated with the cell membrane. Since heat-shock proteins are known to interact with a variety of molecules and since purified HIV-1 particles were described to contain hsp60 molecules, we tested the possibility that a previously described putative receptor for HIV transmembrane protein gp41 is identical to hsp60. The gp41-binding human protein P62 was purified from H9 and Raji cell lysates by a gp41-coupled affinity column. We could show crossreactivity of both polyclonal and monoclonal anti-hsp60 antibodies with the purified P62. In addition we analyzed binding of P18, a soluble gp41 fragment harboring the extracellular domain (Env aa539-684), to recombinant hsp60. Hsp60 bound well to P18-coated ELISA plates whereas HIV-1 surface protein gp120 induced no binding of hsp60. Preincubation of hsp60 with gp41 abolished the binding. The possible role of this molecule as a cofactor in the pathogenesis of HIV disease is discussed.
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PMID:A 60 kD heat-shock protein-like molecule interacts with the HIV transmembrane glycoprotein gp41. 1049 15

We showed in a transient coexpression study that a single proline substitution for any of the five conserved leucine or isoleucine residues located in the envelope (Env) transmembrane protein gp41 zipper motif of the human immunodeficiency virus type 1 dominantly interferes with wild-type Env-mediated viral infectivity. In the present study, we intended to explore the feasibility of developing a genetic anti-HIV strategy targeting the zipper motif. Stable HeLa-CD4-LTR-beta-gal clones that harbored silent copies of Tat-regulated expression cassettes encoding the zipper motif Env mutants were first generated. Expression of any of the five Env mutants in transfectants interfered with exogenously expressed homologous HXB2 Env-mediated cytopathic effects. Mutant transfectants 566, 573, and 580 were further examined. Viral transmission mediated by the laboratory-adapted T cell-tropic HXB2 and NL4-3 viruses was greatly reduced in these transfectants compared with that observed in the env-defective control deltaKS and wt env transfectants. Moreover, viral replication mediated by the NL4-3 virus and a macrophage-tropic ADA-GG virus was delayed or reduced in human T cells harboring the mutant 566 or 580 env construct as opposed to those observed in cells harboring the control deltaKS or mutant 573 env construct. The wt and mutant Env proteins formed a hetero-oligomer when they were coexpressed. These results demonstrate that zipper motif Env mutants 566 and 580 confer an anti-HIV state to the host CD4+ cells, which indicates that dominant inhibitory mutants targeting the gp41 zipper motif might function as genetic anti-HIV agents to combat HIV-1 infection.
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PMID:Conferral of an antiviral state to CD4+ cells by a zipper motif envelope mutant of the human immunodeficiency virus type 1 transmembrane protein gp41. 1051 58

Retroviral vectors derived from amphotropic murine leukemia viruses (MLV) mediate gene transfer into almost all human cells and are thus not suitable for in vivo applications in gene therapy in which cell-specific gene delivery is required. We and others recently reported the generation of MLV-derived vectors pseudotyped by variants of the envelope glycoproteins (Env) of human immunodeficiency virus type 1 (HIV-1), thus displaying the CD4-dependent tropism of the parental lentivirus (Mammano et al., 1997, J. Virol. 71, 3341-3345; Schnierle et al., 1997, Proc. Natl. Acad. Sci. USA 76, 8640-8645). However, because of their HIV-1-derived envelopes these vectors are neutralized by HIV-specific antibodies present in some infected patients. To circumvent this problem, we pseudotyped MLV capsid particles with variants of Env proteins derived from the apathogenic simian immunodeficiency virus (SIVagm) of African green monkeys (AGM; Chlorocebus pygerythrus). Truncation of the C-terminal domain of the transmembrane protein was found to be necessary to allow formation of infectious pseudotype vectors. These [MLV(SIVagm)] vectors efficiently transduced various human CD4-expressing cell lines using the coreceptors CCR5 and Bonzo to enter target cells. Moreover, they were resistant to neutralization by antibodies directed against HIV-1. Therefore, [MLV(SIVagm)] vectors will be useful to study the mechanisms of SIVagm cell entry and for the selective gene transfer into CD4+ T-cells of AIDS patients.
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PMID:MLV-derived retroviral vectors selective for CD4-expressing cells and resistant to neutralization by sera from HIV-infected patients. 1066 18

The characterization of a discontinuous epitope in the C5 region of the HIV envelope protein HIV-gp120, recognized by 1331A, a human mAb, is reported. Regions involved in affinity binding in the HIV-gp120 molecule were identified by epitope excision/extraction methods followed by matrix assisted laser desorption-time of flight mass spectrometry. In epitope excision, the protein is bound in its native conformation to an immobilized Ab and then digested with proteolytic enzymes. In epitope extraction, the protein is first digested and subsequently allowed to react with the Ab. A series of proteolytic digestions of the 1331A/HIV-gp120 complex allowed the identification of protected amino acids in two noncontinuous regions of the C5 region of HIV-gp120. Interaction of the Ab with amino acids I487 and E507 of HIV-gp120 is essential for efficient binding. This is the first application of this approach for the identification and characterization of a discontinuous epitope. The results are consistent with molecular modeling results, indicating that these amino acids are located on opposite sides of a hydrophobic pocket. This pocket is thought to be of importance for the interaction of HIV-gp120 with the transmembrane protein HIV-gp41.
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PMID:Mass spectrometric characterization of a discontinuous epitope of the HIV envelope protein HIV-gp120 recognized by the human monoclonal antibody 1331A. 1075 11


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