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At least 19 recordsLinked to original sources
PubMed1993

Conversion of an immunogenic human immunodeficiency virus (HIV) envelope synthetic peptide to a tolerogen in chimpanzees by the fusogenic domain of HIV gp41 envelope protein.

The fusogenic (F) domain of human immunodeficiency virus (HIV) gp41 envelope (env) protein has sequence similarities to many virus and mediates the fusion of HIV-infected cells. During a survey of the immunogenicity of HIV env peptides in chimpanzees, we have observed that HIV peptide immunogenicity was dramatically altered by the NH2-terminal synthesis of the gp41 F domain to an otherwise immunogenic peptide. We compared two hybrid peptide types comprised of T helper (Th) and B cell epitopes of HIV gp120 env protein for their immunogenicity in chimpanzees. The Th-B epitope hybrid peptides contained the HIV gp120 Th cell determinant, T1 (amino acids [aa] 428-440)-synthesized NH2 terminal to gp120 V3 loop peptides, which contain B cell epitopes that induce anti-HIV-neutralizing antibodies (SP10IIIB [aa 303-321] and SP10IIIB [A] [aa 303-327]). The F-Th-B peptide contained the HIV gp41 F domain of HIVIIIB gp41 (aa 519-530)-synthesized NH2 terminal to the Th-B peptide. Whereas Th-B peptides were potent immunogens for chimpanzee antibody and T cell-proliferative responses, the F-Th-B peptide induced lower anti-HIV gp120 T and B cell responses. Moreover, immunization of chimpanzees with F-Th-B peptide but not Th-B peptides induced a significant decrease in peripheral blood T lymphocytes (mean decrease during immunization, 52%; p < 0.02). Chimpanzees previously immunized with F-Th-B peptide did not respond well to immunization with Th-B peptide with T or B cell responses to HIV peptides, demonstrating that the F-Th-B peptide induced immune hyporesponsiveness to Th and B HIV gp120 env determinants. These observations raise the hypothesis that the HIV gp41 env F domain may be a biologically active immunoregulatory peptide in vivo, and by an as yet uncharacterized mechanism, promotes primate immune system hyporesponsiveness to otherwise immunogenic peptides.

Amino Acid Sequence↗
PubMed1989

Antibody-dependent cellular cytotoxicity is directed against both the gp120 and gp41 envelope proteins of HIV.

To define the target antigens for antibody-dependent cellular cytotoxicity (ADCC), assays were performed using affinity-purified human immunoglobulin (Ig) or polyclonal rabbit sera directed against specific proteins of HIV. ADCC was not found using affinity-purified anti-core (p25) human Ig or sera obtained from rabbits hyper-immunized with recombinant p25. However, when affinity-purified human Ig or rabbit antisera specific for the envelope glycoproteins, gp120 or gp41, were used in ADCC assays, killing of HIV-infected cells was observed. These results indicate that antibodies in the infected individual that mediate ADCC are directed against both the gp120 and gp41 HIV envelope proteins and not against the viral core protein.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1995

An approach for an immunoaffinity AIDS sensor using the conservative region of the HIV envelope protein (gp41) and its monoclonal antibody.

A monoclonal antibody for the conservative region of gp41, which is one of the HIV envelope proteins, was produced. The antigen determining site of gp41 was examined using the epitope mapping technique, followed by an enzyme linked immunosorbent assay. Some peptides had comparable affinities for the monoclonal antibody, but the peptide EGIEE, having a slightly weaker immunoaffinity than gp41, was the most preferable for the construction of an immunoaffinity AIDS sensor. For the detection of gp41, EGIEE was labelled with catalase and used as a mimic antigen; it was bound to the antibody present on an immuno-membrane and, due to the replacement reaction of the mimic antigen by gp41, indirect quantitative measurement of gp41 was possible using an oxygen electrode. Anti-gp41 antibody was also detected using a mimic antibody, which was chemically modified with polyethylene glycol. An immunoaffinity AIDS sensor was constructed using the mimic molecules which were tailored to have a suitable immunoaffinity for HIV antigen and/or antibody.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Interaction of a basic amphipathic peptide from the carboxyterminal part of the HIV envelope protein gp41 with negatively charged lipid surfaces.

The interaction of the positively charged synthetic amphipathic peptide fragment gp41(828) corresponding to a segment from the carboxyterminal region of the HIV envelope glycoprotein gp41 with lipid monolayers spread at the air-water interface has been studied by film balance measurements. The peptide itself does not form a stable monolayer but interacts with phospholipids spread together on the aqueous surface. Upon compression of a mixed phosphatidylcholine-peptide monolayer the peptide is irreversibly squeezed out of the lipid-peptide monolayer. In contrast, with negatively charged phosphatidylglycerol stable lipid-peptide monolayers are formed even in the presence of up to 30 mol% peptide. The monolayer may be expanded and compressed repeatedly without significant loss of substance. After addition of calcium ions to the subphase of a phosphatidylglycerol-peptide monolayer the peptide is to some extent excluded from the monolayer. In contrast to phosphatidylcholine monolayers this process is partly reversible and the excluded material is reincorporated into the film during subsequent expansion. We conclude that attached to the headgroups of the lipid monolayer a peptide-layer stabilized at the surface by electrostatic interactions is formed. The surface action may lead to rigidified lipid-peptide domains causing an increased membrane permeability which might correspond to a cytopathologic function of the protein fragment.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2000

The effect of lipid composition and physical state of phospholipid monolayer on the binding and incorporation of a basic amphipathic peptide from the C-terminal region of the HIV envelope protein gp41.

The interaction of a peptide identical to the carboxy terminal region of the envelope glycoprotein gp41(828) of HIV with negatively charged phospholipids in a monolayer was studied by a Wilhelmy film balance. No significant interaction of the peptide with a monolayer composed of pure neutral but a strong affinity to negatively charged phospholipids could be observed. In mixed phospholipid monolayers the binding of the gp41(828) is primarily limited by the amount of acidic phospholipids. The physical state of the monolayer is another important parameter for binding. Clustering of negatively charged phospholipids and the surface pressure are crucial. Ca(2+) ions strongly interfere with the peptide-lipid interaction up to complete abolishment. The effects observed are dependent on the nature of the acidic lipid. Phosphatidylglycerol was found to be more sensitive than phosphatidylserine. The significance of the results for processes like virus assembly and budding will be discussed.

Amino Acid Sequence↗
PubMed1998

Antigenic characterization of HIV-1 gp41 binding proteins.

The envelope protein HIV-1 gp41 has been shown to exert various effects on human T-cells, B-cells and monocytes like inhibition of cell proliferation, modulation of MHC expression and cytokine production. In contrast to gpl20, where several receptor molecules have been identified, the receptor for gp41 is still unknown. Using a sepharose column, coupled with recombinant soluble gp41, (rsgp41; Env amino acids 539-684), five gp41-binding proteins of 37, 45, 50, 62 and 100 kDa had been isolated from lysates of the B-cell line Raji. Two mouse antiserums were generated against the proteins P45 and P62 and were tested against the binding specificity of both antiserums. In Western blot analysis the antiserums recognized two protein bands of 45 and 62 kDa in complete Raji cell lysates, as well as the purified proteins P45 and P62, respectively, but did not show any cross-reaction, indicating that the two proteins do not share any immunological epitopes. Besides, the polyclonal antiserums did not recognize the other gp41-binding proteins P37, P50 and P100. Using the P62 antiserum proteins of the same size as in Raji cell lysates were stained in the lysates of the monocytic cell line U937 and the T-cell line H9, demonstrating distribution of P62 in different blood cells. P45 seems not to be identical to HLA-C which had been shown to bind to gp41. These results indicate, that P45 and P62 are two separate gp41-binding proteins without homology to each other or to the other gp41-binding proteins.

Animals↗
PubMed1989

Theoretically determined three-dimensional structures for amphipathic segments of the HIV-1 gp41 envelope protein.

Three-dimensional computer models for two segments of the C terminus of gp41, the transmembrane AIDS envelope protein, which may form amphipathic alpha-helices, have been generated using structure prediction techniques combined with energy minimization and molecular dynamics simulations. Regions gp41(772-790) and gp41(828-848) of the HXB2 strain of HIV-1 display extraordinarily high hydrophobic moment maxima as alpha-helices and when in an antiparallel conformation exhibit charge complementarity, implying that they may bind with each other and associate with the membrane. The feasibility of this hypothesis was tested in a series of computer simulations of these peptides, extended by several residues to include additional charge pairing. Beginning with a trial structure in the form of antiparallel alpha-helices of segments 770-794 and 824-856, systematic axial rotations and displacements were used to generate alternative initial states. Molecular dynamics simulations with alpha-helical torsional restraints yielded several approximately cylindrical dimeric structures highly stabilized by numerous salt links and other hydrogen bonds. This suggests that these two regions may fold back on each other in antiparallel fashion to form a loop in the tertiary structure over residues 770-856, with the loop closed by membrane-associated amphipathic alpha-helices with charged sides facing each other. We speculate that such structures could aggregate to form channels or otherwise destabilize the membrane, thereby contributing to the cytopathic effects of the gp120-gp41 complex.

Amino Acid Sequence↗
PubMed1995

Human complement proteins C3b, C4b, factor H and properdin react with specific sites in gp120 and gp41, the envelope proteins of HIV-1.

Recently we reported the basic phenomenon of an interaction between the envelope glycoproteins of HIV-1 gp120 and gp41 and components of the human complement system, i.e. activated C4 (C4b) and activated C3 (C3b) and the complement regulator proteins factor H and properdin. In this study we analyze these interactions in detail. Using 46 overlapping peptides of gp120 attached to microtiter plates, binding of activated human C3 to 6 regions in gp120 was found (aa 100-129, 161-190, 231-250, 301-328, 410-449, 470-499). In competition assays with soluble peptides, representatives of four of these regions were capable to partially inhibit C3b binding to immobilized gp120. Activated human C4 interacted only with peptides covering aa 410-449, but both in direct binding assays and fluid phase inhibition studies. The multi-reactivity of gp120 with C3b was also supported by the fact that gp120 agglutinated erythrocytes coated with C3b. Guided by partial aa sequence homology of gp120 and human C4b binding protein (C4bp) as well as human properdin we detected binding of anti-properdin to aa 100-129 in gp120 and of anti-C4bp to aa 410-449 in gp120. This cross-reactivity was also confirmed by a monoclonal antibody directed against aa 416-443 of gp120, which could be shown to bind C4bp. Interestingly, aa 310-328, part of the V3-loop, were found to show an aa sequence similarity to human complement receptor type 3 (alpha-chain). Consequently, of the 4 (or possibly 6) interaction sites of gp120 with activated human C3, 3 may bind due to imitation of either properdin, CR3 or C4bp. In addition to C4b and C3b, we detected interaction of factor H with gp120; it selectively bound to aa 102-129. Using 14 overlapping peptides of gp41 attached to plates, we identified 4 areas in gp-41 (aa 561-585, 587-605, 615-635, 651-675) which bound human factor H. All of them except the first region partially inhibited factor H binding to gp41 in competition assays with soluble peptides. Properdin bound only to 2 regions (aa 584-614, 651-675). The first 3 sites in gp41 were already shown by us to share homology to sites in human C3. The region around aa 651-675 now also turned out to be similar to human C3. These data demonstrate that the interaction of both, gp120 and gp41, with the complement system is polyvalent and complex.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed2000

N36, a synthetic N-terminal heptad repeat domain of the HIV-1 envelope protein gp41, is an activator of human phagocytes.

Human immunodeficiency virus type 1 (HIV-1) envelope protein gp41 mediates viral fusion with human host cells. In this study we show that N36, a synthetic peptide derived from the N-terminus of gp41, induced directional migration and calcium mobilization in human monocytes and neutrophils. The activity of N36 on phagocytes was pertussis toxin sensitive, suggesting involvement of a Gi-coupled seven-transmembrane receptor(s). Since high concentrations of the bacterial chemotactic peptide fMet-Leu-Phe (fMLF) partially desensitized the calcium mobilizing activity of N36 in phagocytes, we postulated that N36 might use a low-affinity fMLF receptor. By using cells stably expressing fMLF receptor FPR or FPRL1, we demonstrate that N36 uses FPRL1 as a functional receptor. Our results suggest that HIV-1 gp41 may contain a fragment(s) that activates the innate host immune cells through FPRL1. Since the activation of FPRL1 in monocytes has been shown to heterologously desensitize chemokine receptors, the reduced phagocyte response to chemoattractants seen in AIDS patients may be attributed, at least in part, to heterologous desensitization.

Anti-HIV Agents↗
PubMed1998

Evidence that a prominent cavity in the coiled coil of HIV type 1 gp41 is an attractive drug target.

Synthetic C peptides, corresponding to the C helix of the HIV type 1 (HIV-1) gp41 envelope protein, are potent inhibitors of HIV-1 membrane fusion. One such peptide is in clinical trials. The crystal structure of the gp41 core, in its proposed fusion-active conformation, is a trimer of helical hairpins in which three C helices pack against a central coiled coil. Each C helix shows especially prominent contacts with one of three symmetry-related, hydrophobic cavities on the surface of the coiled coil. We show that the inhibitory activity of the C peptide C34 depends on its ability to bind to this coiled-coil cavity. Moreover, examining a series of C34 peptide variants with modified cavity-binding residues, we find a linear relationship between the logarithm of the inhibitory potency and the stability of the corresponding helical-hairpin complexes. Our results provide strong evidence that this coiled-coil cavity is a good drug target and clarify the mechanism of C peptide inhibition. They also suggest simple, quantitative assays for the identification and evaluation of analogous inhibitors of HIV-1 entry.

Amino Acid Sequence↗
PubMedDate not supplied

The complex antigenicity of a small external region of the C-terminal tail of the HIV-1 gp41 envelope protein: a lesson in epitope analysis.

The newly discovered external tail loop within the C-terminal tail of the gp41 transmembrane subunit of the HIV-1 envelope protein comprises approximately 40 residues, and within this are 18-residues ((734)PDRPEGIEEEGGERDRDR(751)) that include three antibody-reactive regions. The antigenicity is complex, and changes according to the biological context of the gp41. It is thus of interest both to the HIV specialist and protein immunologists. The antibody-reactive region, centred on the sequence ERDRD, encompasses three distinct epitopes which are expressed in different combinations on infected cells, wt virions, prefusion virion-cell complexes, and a neutralising antibody escape mutant virion. In addition ERDRD-specific antibodies have one or more antiviral activities, and variously neutralise the infectivity of free virions, neutralise virions already attached to the target cell, reduce the production of infectious progeny, and inhibit the ability of infected cells to fuse with non-infected cells. Antibodies to PDRPEG and IEEE have no apparent antiviral activity even though the footprints of the IEEE- and ERDRD-specific antibodies overlap. This review marshals the available experimental data with the aim of understanding the significance of the gp41 tail loop to the HIV-1 life cycle, and its relevance to potential anti-viral measures. There are lessons here, too, that are relevant to the comprehension of the antigenicity of short protein segments in general.

Amino Acid Sequence↗
PubMed1995

Interaction of several complement proteins with gp120 and gp41, the two envelope glycoproteins of HIV-1.

OBJECTIVE: To study the binding of human complement proteins to gp41 and gp120 of HIV-1. METHODS: The interaction of complement proteins with gp41 and gp120 and their effect on the gp41-gp120 complex in enzyme-linked immunosorbent assays (ELISA) and on stably transfected Schneider-2 cells expressing a gp41-gp120 complex was investigated. The molecular basis of these interactions was analysed by computer-supported sequence analysis. RESULT: gp41 strongly binds human complement regulatory proteins factors H and properdin, and weakly binds factors I and B. The binding occurs with recombinant soluble (rs) gp41 fixed on ELISA plates as well as gp41-gp120 complex expressed on Schneider-2 cells. The basis for this binding potential might be an amino-acid (aa) sequence of gp41 displaying homologies to sites in human C3. rgp120 also binds C3(H2O), a C3b-like form of C3, and C4b. These binding features of gp120 can be explained by homology of constant region (CR) 4 in gp120 to sites in C4b binding protein. Additionally, CR1 in gp120 exhibits a weak similarity to human properdin. Preincubation of rsgp41 with either factor H or properdin, and of rgp120 with C3b or C4b affected the interaction between rsgp41 and rgp120. Incubation of Schneider-2 cells, expressing a functional gp41-gp120 complex, with factor H reduced the detectable amount of gp120. This effect was similar to that induced by soluble CD4. CONCLUSION: These results strongly suggest that HIV-1 envelope proteins interact with human complement proteins. Additionally, C3b-like features of gp41 and the C3b/C4b binding structures in gp120 may affect the non-covalent association between gp41 and gp120.

Amino Acid Sequence↗
PubMed2001

Structure and interaction with membrane model systems of a peptide derived from the major epitope region of HIV protein gp41: implications on viral fusion mechanism.

The HIV-1 gp41 envelope protein mediates entry of the virus into the target cell by promoting membrane fusion. With a view toward possible new insights into viral fusion mechanisms, we have investigated by infrared, fluorescence, and nuclear magnetic resonance spectroscopies and calorimetry a fragment of 19 amino acids corresponding to the immunodominant region of the gp41 ectodomain, a highly conserved sequence and major epitope. Information on the structure of the peptide both in solution and in the presence of model membranes, its incorporation and location in the phospholipid bilayer, and the modulation of the phase behavior of the membrane has been gathered. Here we demonstrate that the peptide binds and interacts with negatively charged phospholipids, changes its conformation in the presence of a membraneous medium, and induces leakage of vesicle contents as well as a new phospholipid phase. These characteristics might be important for the formation of the fusion-active gp41 core structure, promoting the close apposition of the two viral and target-cell membranes and therefore provoking fusion.

Amino Acid Sequence↗
PubMed2000

HIV-1 envelope protein gp41 modulates expression of interleukin-10 and chemokine receptors on monocytes, astrocytes and neurones.

OBJECTIVE: To analyse the effect of HIV-1 transmembrane protein gp41 on cytokine production and chemokine receptor expression in blood and brain. DESIGN: Because previous results had demonstrated that recombinant gp41 contributes to HIV-induced dysfunction of blood immune cells we investigated its effect on interleukin (IL)-10 synthesis and expression of the HIV coreceptors CCR5 and CXCR4 in different human brain cells. METHODS: Astrocytic, microglial and neuronal cell lines were incubated with the extracellular domain of gp41 (aa565-647). Secretion of IL-10 into the medium was measured by ELISA. Chemokine receptor expression was analysed by fluorescence activated cell sorting and by RT-PCR. RESULTS: Incubation of the astrocytic cell line U87 with gp41 induced more than a 10 fold up-regulation of IL-10 secretion. This modulation was shown to be time- and dose-dependent. Use of inhibitors for different signal transduction pathways indicated a similar transduction cascade for the alteration of IL-10 production in astrocytes as in monocytes with participation of cAMP/adenylate cyclase and activation of p70S6 kinase. To a lesser extent IL-10 synthesis was also up-regulated by gp41 in the neuronal cell line SK-N-SH. In all cell types up-regulation of IL-10 paralleled by an enhanced expression of the chemokine receptor and HIV-1 coreceptor CCR5. This up-regulation was driven by IL-10 as shown by use of an IL-10 antibody. Expression of the chemokine receptor CXCR4 was only slightly altered. CONCLUSIONS: These findings suggest a role for gp41 in the modulation of brain-specific host defence, cell migration and cell infectivity by HIV.

Astrocytes↗
PubMed2004

Sedimentation velocity studies of the high-molecular weight aggregates of the HIV gp41 ectodomain.

Accumulation of the HIV envelope protein gp41 is observed in the brain tissues of patients suffering from HIV-associated dementia. Previously, we have shown by electron microscopy that the extracellular domain of SIV gp41, which is analogous to that of HIV, forms high-molecular weight aggregates in vitro, and we have postulated that such high-molecular weight aggregates are responsible for neurological damage in a manner similar to protein deposition diseases such as Alzheimer's and the prion diseases. In this manuscript, we have characterized the self-association of the HIV gp41 ectodomain by sedimentation velocity. We show that discreet species of the gp41 high-molecular weight aggregates are present. The maximum population occurs at 20 S, which corresponds to ~5 trimers of gp41, suggesting that five trimers are required for nucleation of the high-molecular weight aggregates. The concentration dependence of the gp41 self-association indicates that it occurs by mass action. The temperature dependence of gp41 self-association suggests that it is driven by entropy, indicating that intermolecular hydrophobic interactions between trimers of gp41 are driving the association.

AIDS Dementia Complex↗
PubMed2005

NK cytotoxicity against CD4+ T cells during HIV-1 infection: a gp41 peptide induces the expression of an NKp44 ligand.

HIV infection leads to a state of chronic immune activation and progressive deterioration in immune function, manifested most recognizably by the progressive depletion of CD4+ T cells. A substantial percentage of natural killer (NK) cells from patients with HIV infection are activated and express the natural cytotoxicity receptor (NCR) NKp44. Here we show that a cellular ligand for NKp44 (NKp44L) is expressed during HIV-1 infection and is correlated with both the progression of CD4+ T cell depletion and the increase of viral load. CD4+ T cells expressing this ligand are highly sensitive to the NK lysis activity mediated by NKp44+ NK cells. The expression of NKp44L is induced by the linear motif NH2-SWSNKS-COOH of the HIV-1 envelope gp41 protein. This highly conserved motif appears critical to the sharp increase in NK lysis of CD4+ T cells from HIV-infected patients. These studies strongly suggest that induction of NKp44L plays a key role in the lysis of CD4+ T cells by activated NK cells in HIV infection and consequently provide a framework for considering how HIV-1 may use NK cell immune surveillance to trigger CD4+ T cells. Understanding this mechanism may help to develop future therapeutic strategies and vaccines against HIV-1 infection.

Amino Acid Motifs↗
PubMed2004

A trimeric HIV-1 fusion peptide construct which does not self-associate in aqueous solution and which has 15-fold higher membrane fusion rate.

A peptide construct (FPtr) was synthesized which mimics the biologically relevant topology of fusion peptide (FP) domains of the trimeric HIV-1 gp41 envelope protein. The FP domains play a critical role in gp41-catalyzed fusion of viral and host cell membranes which is a key step in viral infection. The FPtr construct contains three FP strands chemically bonded at their C-termini through lysine side chains. Analytical ultracentrifugation demonstrated that FPtr does not self-associate in aqueous solution and therefore models the expected FP topology of gp41. Comparative functional fusion assays were carried out using FPtr, FPdm (a cross-linked FP dimer construct), and FPmn (FP monomer). The derived fusion rate constants order ktr > kdm > kmn, and the ratio ktr/kmn has values in the range of 15-40. These results suggest that there is strong correlation of the fusion rate with the biologically relevant trimeric FP topology.

Amino Acid Sequence↗
PubMed2005

Mutations conferring resistance to human immunodeficiency virus type 1 fusion inhibitors are restricted by gp41 and Rev-responsive element functions.

One of the human immunodeficiency virus (HIV) envelope proteins, gp41, plays a key role in HIV fusion. A gp41-derived peptide, T-20, efficiently inhibits HIV fusion and is currently approved for treatment of HIV-infected individuals. Although resistant variants have been reported, the mechanism of the resistance remains to be defined. To elucidate the mechanism in detail, we generated variants resistant to C34, a peptide derived from the gp41 carboxyl terminus heptad repeat (C-HR) in vitro. The resistant variants had a 5-amino-acid deletion in gp120 and a total of seven amino acid substitutions in gp41. Binding assays revealed that an I37K substitution in the N-terminal heptad repeat (N-HR) impaired the binding of C34, whereas an N126K substitution in the C-HR enhanced the binding to mutated N-HR, indicating that both mutations were directly involved in resistance. On the other hand, substitutions for A30 and D36 seemed to be secondary mutations, located complementary to each other in the Rev-responsive element (RRE), and were mutated simultaneously to maintain the secondary structure of the RRE that was impaired by the mutations at I37. Thus, HIV acquired resistance to C34 by mutations in N-HR, which directly interacted with C34. However, since this region also encoded the RRE, additional mutations were required to maintain viral replication. These results suggest that HIV fusion is one of the attractive targets for HIV chemotherapy.

Amino Acid Sequence↗