Inhibition of HIV-1-Induced Cytopathogenicity, Syncytium Formation, and Virus-Cell Binding by Naphthalenedisulphonic Acids through Interaction with the Viral Envelope gp120 Glycoprotein

1993 ◽  
Vol 4 (4) ◽  
pp. 229-234 ◽  
Author(s):  
M. Baba ◽  
D. Schols ◽  
P. Mohan ◽  
E. De Clercq ◽  
S. Shigeta
Keyword(s):  
Monoclonal Antibody ◽  
Syncytium Formation ◽  
Viral Envelope ◽  
Flow Cytometric ◽  
Gp120 Antigen ◽  
Immunodeficiency Virus ◽  
Glycoprotein Gp120 ◽  
Gp120 Glycoprotein ◽  
Hiv 1

Bis-naphthalenedisulphonic acid derivatives with a biphenyl spacer, 4,4′-[4,4′-biphenyldiylbis(sulphonyl-amino)]bis(5-hydroxy-2,7-naphthalenedisulphonic acid) and 3,3′-[4,4′-biphenyldiylbis(sulphonyl-amino)]bis(1,5-naphthalenedisulphonic acid), have previously been reported as potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) replication in cell culture. These compounds have also proved inhibitory to syncytium formation in cocultures of MOLT-4 cells with HIV-1-infected HUT-78 cells. They also inhibit the binding of HIV-1 virions to MT-4 cells as determined by a flow cytometric (FACS) method. Further studies on their mechanism of action by the FACS have revealed that the compounds inhibit the binding of anti-gp120 monoclonal antibody to the viral envelope glycoprotein gp120. Binding of OKT4A/Leu3a monoclonal antibody to the cellular CD4 receptor is not affected by the compounds. These results suggest that the anti-HIV-1 activity of the naphthalenedisulphonic acid derivatives can be attributed to inhibition of the gp120-CD4 interaction through binding of the compounds to the viral gp120 antigen.

scholarly journals Mechanism of Human Immunodeficiency Virus Type 1 Resistance to Monoclonal Antibody b12 That Effectively Targets the Site of CD4 Attachment

2009 ◽  
Vol 83 (21) ◽  
pp. 10892-10907 ◽  
Author(s):  
Xueling Wu ◽  
Tongqing Zhou ◽  
Sijy O'Dell ◽  
Richard T. Wyatt ◽  
Peter D. Kwong ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Binding Site ◽  
Contact Surface ◽  
Neutralizing Antibodies ◽  
Viral Envelope ◽  
Contact Sites ◽  
Immunodeficiency Virus ◽  
Cd4 Binding Site ◽  
Hiv 1

ABSTRACT The region of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 that engages its primary cellular receptor CD4 forms a site of vulnerability to neutralizing antibodies. The monoclonal antibody b12 exploits the conservation and accessibility of the CD4-binding site to neutralize many, though not all, HIV-1 isolates. To understand the basis of viral resistance to b12, we used the atomic-level definition of b12-gp120 contact sites to study a panel of diverse circulating viruses. A combination of sequence analysis, computational modeling, and site-directed mutagenesis was used to determine the influence of amino acid variants on binding and neutralization by b12. We found that several substitutions within the dominant b12 contact surface, called the CD4-binding loop, mediated b12 resistance, and that these substitutions resided just proximal to the known CD4 contact surface. Hence, viruses varied in key b12 contact residues that are proximal to, but not part of, the CD4 contact surface. This explained how viral isolates were able to evade b12 neutralization while maintaining functional binding to CD4. In addition, some viruses were resistant to b12 despite minimal sequence variation at b12 contact sites. Such neutralization resistance usually could be reversed by alterations at residues thought to influence the quaternary configuration of the viral envelope spike. To design immunogens that elicit neutralizing antibodies directed to the CD4-binding site, researchers need to address the antigenic variation within this region of gp120 and the restricted access to the CD4-binding site imposed by the native configuration of the trimeric viral envelope spike.

scholarly journals Differential Transmission of Human Immunodeficiency Virus Type 1 by Distinct Subsets of Effector Dendritic Cells

2002 ◽  
Vol 76 (15) ◽  
pp. 7812-7821 ◽  
Author(s):  
Rogier W. Sanders ◽  
Esther C. de Jong ◽  
Christopher E. Baldwin ◽  
Joost H. N. Schuitemaker ◽  
Martien L. Kapsenberg ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Dendritic Cells ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Virus Transmission ◽  
Viral Envelope ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Dendritic cells (DC) support human immunodeficiency virus type 1 (HIV-1) transmission by capture of the virus particle in the mucosa and subsequent transport to the draining lymph node, where HIV-1 is presented to CD4+ Th cells. Virus transmission involves a high-affinity interaction between the DC-specific surface molecule DC-SIGN and the viral envelope glycoprotein gp120 and subsequent internalization of the virus, which remains infectious. The mechanism of viral transmission from DC to T cells is currently unknown. Sentinel immature DC (iDC) develop into Th1-promoting effector DC1 or Th2-promoting DC2, depending on the activation signals. We studied the ability of these effector DC subsets to support HIV-1 transmission in vitro. Compared with iDC, virus transmission is greatly upregulated for the DC1 subset, whereas DC2 cells are inactive. Increased transmission by DC1 correlates with increased expression of ICAM-1, and blocking studies confirm that ICAM-1 expression on DC is important for HIV transmission. The ICAM-1-LFA-1 interaction is known to be important for immunological cross talk between DC and T cells, and our results indicate that this cell-cell contact is exploited by HIV-1 for efficient transmission.

scholarly journals Monitoring Early Fusion Dynamics of Human Immunodeficiency Virus Type 1 at Single-Molecule Resolution

2008 ◽  
Vol 82 (14) ◽  
pp. 7022-7033 ◽  
Author(s):  
Terrence M. Dobrowsky ◽  
Yan Zhou ◽  
Sean X. Sun ◽  
Robert F. Siliciano ◽  
Denis Wirtz
Keyword(s):  
Human Immunodeficiency Virus ◽  
Tensile Strength ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Single Molecule ◽  
Viral Envelope ◽  
Host Cells ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The fusion of human immunodeficiency virus type 1 (HIV-1) to host cells is a dynamic process governed by the interaction between glycoproteins on the viral envelope and the major receptor, CD4, and coreceptor on the surface of the cell. How these receptors organize at the virion-cell interface to promote a fusion-competent site is not well understood. Using single-molecule force spectroscopy, we map the tensile strengths, lifetimes, and energy barriers of individual intermolecular bonds between CCR5-tropic HIV-1 gp120 and its receptors CD4 and CCR5 or CXCR4 as a function of the interaction time with the cell. According to the Bell model, at short times of contact between cell and virion, the gp120-CD4 bond is able to withstand forces up to 35 pN and has an initial lifetime of 0.27 s and an intermolecular length of interaction of 0.34 nm. The initial bond also has an energy barrier of 6.7 kB T (where kB is Boltzmann's constant and T is absolute temperature). However, within 0.3 s, individual gp120-CD4 bonds undergo rapid destabilization accompanied by a shortened lifetime and a lowered tensile strength. This destabilization is significantly enhanced by the coreceptor CCR5, not by CXCR4 or fusion inhibitors, which suggests that it is directly related to a conformational change in the gp120-CD4 bond. These measurements highlight the instability and low tensile strength of gp120-receptor bonds, uncover a synergistic role for CCR5 in the progression of the gp120-CD4 bond, and suggest that the cell-virus adhesion complex is functionally arranged about a long-lived gp120-coreceptor bond.

scholarly journals Human Immunodeficiency Virus Type 1 (HIV-1) Diversity at Time of Infection Is Not Restricted to Certain Risk Groups or Specific HIV-1 Subtypes

2004 ◽  
Vol 78 (13) ◽  
pp. 7279-7283 ◽  
Author(s):  
Manish Sagar ◽  
Erin Kirkegaard ◽  
E. Michelle Long ◽  
Connie Celum ◽  
Susan Buchbinder ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Risk Groups ◽  
The United States ◽  
Viral Envelope ◽  
Subtype B ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT African women frequently acquire several genetically distinct human immunodeficiency virus type 1 (HIV-1) variants from a heterosexual partner, whereas the acquisition of multiple variants appears to be rare in men. To determine whether newly infected individuals in other risk groups acquire genetically diverse viruses, we examined the viral envelope sequences in plasma samples from 13 women and 4 men from the United States infected with subtype B viruses and 10 men from Kenya infected with non-subtype B viruses. HIV-1 envelope sequences differed by more than 2% in three U.S. women, one U.S. man, and one Kenyan man near the time of seroconversion. These findings suggest that early HIV-1 genetic diversity is not exclusive to women from Africa or to infection with any particular HIV-1 subtype.

scholarly journals Baseline Resistance of Primary Human Immunodeficiency Virus Type 1 Strains to the CXCR4 Inhibitor AMD3100

2008 ◽  
Vol 82 (23) ◽  
pp. 11695-11704 ◽  
Author(s):  
Jessamina E. Harrison ◽  
Jonathan B. Lynch ◽  
Luz-Jeannette Sierra ◽  
Leslie A. Blackburn ◽  
Neelanjana Ray ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Antiviral Agents ◽  
Viral Envelope ◽  
Cxcr4 Antagonist ◽  
Immunodeficiency Virus ◽  
Env Protein ◽  
Hiv 1

ABSTRACT We screened a panel of R5X4 and X4 human immunodeficiency virus type 1 (HIV-1) strains for their sensitivities to AMD3100, a small-molecule CXCR4 antagonist that blocks HIV-1 infection via this coreceptor. While no longer under clinical development, AMD3100 is a useful tool with which to probe interactions between the viral envelope (Env) protein and CXCR4 and to identify pathways by which HIV-1 may become resistant to this class of antiviral agents. While infection by most virus strains was completely blocked by AMD3100, we identified several R5X4 and X4 isolates that exhibited plateau effects: as the AMD3100 concentration was increased, virus infection and membrane fusion diminished to variable degrees. Once saturating concentrations of AMD3100 were achieved, further inhibition was not observed, indicating a noncompetitive mode of viral resistance to the drug. The magnitude of the plateau varied depending on the virus isolate, as well as the cell type used, with considerable variation observed when primary human T cells from different human donors were used. Structure-function studies indicated that the V1/V2 region of the R5X4 HIV-1 isolate DH12 was necessary for AMD3100 resistance and could confer this property on two heterologous Env proteins. We conclude that some R5X4 and X4 HIV-1 isolates can utilize the AMD3100-bound conformation of CXCR4, with the efficiency being influenced by both viral and host factors. Baseline resistance to this CXCR4 antagonist could influence the clinical use of such compounds.

scholarly journals A rat CD4 mutant containing the gp120-binding site mediates human immunodeficiency virus type 1 infection.

1993 ◽  
Vol 177 (4) ◽  
pp. 949-954 ◽  
Author(s):  
J H Simon ◽  
C Somoza ◽  
G A Schockmel ◽  
M Collin ◽  
S J Davis ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Syncytium Formation ◽  
Gp120 Binding ◽  
Ability To Act ◽  
Immunodeficiency Virus ◽  
Inhibitory Antibodies ◽  
Hiv 1

CD4 is the primary receptor for the human immunodeficiency virus type 1 (HIV-1). Early mutational studies implicated a number of residues of CD4, centered in the region 41-59, in binding to gp120. However, further mutational analyses, together with studies using inhibitory antibodies or CD4-derived peptides, have suggested that other regions of CD4 are also involved in binding or postbinding events during infection. To resolve these ambiguities, we used rat CD4 mutants in which particular regions were replaced with the corresponding sequence of human CD4. We have previously shown that some of these are able to bind HIV-1 gp120, and here we test their ability to act as functional receptors. We find that the presence of human CD4 residues 33-62 is enough to confer efficient receptor function to rat CD4, and we conclude that it is unlikely that regions of CD4 outside this sequence are involved in specific interactions with HIV-1 during either infection or syncytium formation.

scholarly journals An Unrelated Monoclonal Antibody Neutralizes Human Immunodeficiency Virus Type 1 by Binding to an Artificial Epitope Engineered in a Functionally Neutral Region of the Viral Envelope Glycoproteins

2005 ◽  
Vol 79 (9) ◽  
pp. 5616-5624 ◽  
Author(s):  
Xinping Ren ◽  
Joseph Sodroski ◽  
Xinzhen Yang
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Envelope Glycoprotein ◽  
Virus Entry ◽  
Neutralizing Antibody ◽  
Viral Envelope ◽  
Epitope Tag ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Neutralizing antibodies often recognize regions of viral envelope glycoproteins that play a role in receptor binding or other aspects of virus entry. To address whether this is a necessary feature of a neutralizing antibody, we identified the V4 region of the gp120 envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) as a sequence that is tolerant of drastic change and thus appears to play a negligible role in envelope glycoprotein function. An artificial epitope tag was inserted into the V4 region without a significant effect on virus entry or neutralization by antibodies that recognize HIV-1 envelope glycoprotein sequences. An antibody directed against the artificial epitope tag was able to neutralize the modified, but not the wild-type, HIV-1. Thus, the specific target of a neutralizing antibody need not contribute functionally to the process of virus entry.

scholarly journals Reverse Immunology Approach to Define a New HIV-gp41-Neutralizing Epitope

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Karim Dorgham ◽  
Nicolas Pietrancosta ◽  
Amel Affoune ◽  
Olivier Lucar ◽  
Tahar Bouceba ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Molecular Design ◽  
Docking Studies ◽  
Viral Envelope ◽  
Broadly Neutralizing Antibodies ◽  
Immunodeficiency Virus ◽  
Surface Envelope ◽  
Hiv 1

The design of immunogens susceptible to elicit potent and broadly neutralizing antibodies against the human immunodeficiency virus type 1 (HIV-1) remains a veritable challenge in the course of vaccine development. Viral envelope proteins adopt different conformational states during the entry process, allowing the presentation of transient neutralizing epitopes. We focused on the highly conserved 3S motif of gp41, which is exposed to the surface envelope in its trimeric prefusion state. Vaccination with a W614A-modified 3S peptide induces in animals neutralizing anti-HIV-1 antibodies among which we selected clone F8. We used F8 as bait to select for W614A-3S phage-peptide mimics. Binding and molecular docking studies revealed that F8 interacts similarly with W614A-3S and a Mim_F8-1 mimotope, despite their lack of sequence homology, suggesting structural mimicry. Finally, vaccination of mice with the purified Mim_F8-1 phage elicited HIV-1-neutralizing antibodies that bound to the cognate W614A-3S motif. Collectively, our findings provide new insights into the molecular design of immunogens to elicit antibodies with neutralizing properties.

Tin Protoporphyrin IX Used in Control of Heme Metabolism in Humans Effectively Inhibits HIV-1 Infection

1994 ◽  
Vol 5 (5) ◽  
pp. 322-330 ◽  
Author(s):  
A. R. Neurath ◽  
N. Strick ◽  
K. Lin ◽  
A. K. Debnath ◽  
S. Jiang
Keyword(s):  
Protoporphyrin Ix ◽  
V3 Loop ◽  
Gp 120 ◽  
Loop Sequence ◽  
Immunodeficiency Virus ◽  
Cd4 Binding Site ◽  
Glycoprotein Gp120 ◽  
Tin Protoporphyrin ◽  
Hiv 1

Recent observations indicated that several porphyrins bound to the V3 loop of the envelope glycoprotein gp120 of the human immunodeficiency virus type 1 (HIV-1) and inhibited infection of cells by HIV-1. The tin derivative of protoporphyrin IX (Sn-PTP-IX) has already been used clinically in humans to suppress hyperbilirubinemia. It was therefore of interest to determine whether Sn-PTP-IX has anti-HIV-1 activity. It is demonstrated here that Sn-PTP-IX effectively inhibited infection by several HIV-1 isolates (HIB, MN, RF, SF-2 and two isolates resistant to azidothymidine). This was surprising, since earlier studies indicated that incorporation of other metals into porphyrins markedly decreased their antiviral activity. Sn-PTP-IX blocked the binding to gp120 of anti-V3-loop-specific antibodies and of monoclonal antibodies specific for the CD4 binding site on gp120. The latter effect appeared to be allosteric and was not observed with a deletion mutant of gp 120 lacking the V3 loop sequence. This suggests that Sn-PTP-IX binds to the V3 loop and distorts the native conformation of the HIV-1 envelope, thereby preventing infection. These results merit the consideration of Sn-PTP-IX as a prophylactic and chemotherapeutic agent against HIV-1.

scholarly journals Cross-Reactive Human Immunodeficiency Virus Type 1-Neutralizing Human Monoclonal Antibody That Recognizes a Novel Conformational Epitope on gp41 and Lacks Reactivity against Self-Antigens

2008 ◽  
Vol 82 (14) ◽  
pp. 6869-6879 ◽  
Author(s):  
Mei-Yun Zhang ◽  
Bang K. Vu ◽  
Anil Choudhary ◽  
Hong Lu ◽  
Michael Humbert ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Human Immunodeficiency Virus ◽  
Conformational Epitope ◽  
Heptad Repeat ◽  
Enzyme Linked Immunosorbent Assay ◽  
Human Antibody ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Self Antigens

ABSTRACT Broadly cross-reactive human immunodeficiency virus (HIV)-neutralizing antibodies are infrequently elicited in infected humans. The two best-characterized gp41-specific cross-reactive neutralizing human monoclonal antibodies, 4E10 and 2F5, target linear epitopes in the membrane-proximal external region (MPER) and bind to cardiolipin and several other autoantigens. It has been hypothesized that, because of such reactivity to self-antigens, elicitation of 2F5 and 4E10 and similar antibodies by vaccine immunogens based on the MPER could be affected by tolerance mechanisms. Here, we report the identification and characterization of a novel anti-gp41 monoclonal antibody, designated m44, which neutralized most of the 22 HIV type 1 (HIV-1) primary isolates from different clades tested in assays based on infection of peripheral blood mononuclear cells by replication-competent virus but did not bind to cardiolipin and phosphatidylserine in an enzyme-linked immunosorbent assay and a Biacore assay nor to any protein or DNA autoantigens tested in Luminex assays. m44 bound to membrane-associated HIV-1 envelope glycoproteins (Envs), to recombinant Envs lacking the transmembrane domain and cytoplasmic tail (gp140s), and to gp41 structures containing five-helix bundles and six-helix bundles, but not to N-heptad repeat trimers, suggesting that the C-heptad repeat is involved in m44 binding. In contrast to 2F5, 4E10, and Z13, m44 did not bind to any significant degree to denatured gp140 and linear peptides derived from gp41, suggesting a conformational nature of the epitope. This is the first report of a gp41-specific cross-reactive HIV-1-neutralizing human antibody that does not have detectable reactivity to autoantigens. Its novel conserved conformational epitope on gp41 could be helpful in the design of vaccine immunogens and as a target for therapeutics.

Sign in / Sign up

Export Citation Format

Share Document