Correlation of Maternal Cytophilic Human Immunodeficiency Virus (HIV)-1 V3 Loop Peptide-Specific Antibodies in Infants with Vertical HIV Transmission

ABSTRACT Human immunodeficiency virus (HIV-1) entry into cells is mediated by a trimeric complex consisting of noncovalently associated gp120 (exterior) and gp41 (transmembrane) envelope glycoproteins. The binding of gp120 to receptors on the target cell alters the gp120-gp41 relationship and activates the membrane-fusing capacity of gp41. Interaction of gp120 with the primary receptor, CD4, results in the exposure of the gp120 third variable (V3) loop, which contributes to binding the CCR5 or CXCR4 chemokine receptors. We show here that insertions in the V3 stem or polar substitutions in a conserved hydrophobic patch near the V3 tip result in decreased gp120-gp41 association (in the unliganded state) and decreased chemokine receptor binding (in the CD4-bound state). Subunit association and syncytium-forming ability of the envelope glycoproteins from primary HIV-1 isolates were disrupted more by V3 changes than those of laboratory-adapted HIV-1 envelope glycoproteins. Changes in the gp120 β2, β19, β20, and β21 strands, which evidence suggests are proximal to the V3 loop in unliganded gp120, also resulted in decreased gp120-gp41 association. Thus, a gp120 element composed of the V3 loop and adjacent beta strands contributes to quaternary interactions that stabilize the unliganded trimer. CD4 binding dismantles this element, altering the gp120-gp41 relationship and rendering the hydrophobic patch in the V3 tip available for chemokine receptor binding.

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X4 Human Immunodeficiency Virus Type 1 gp120 Down-Modulates Expression and Immunogenicity of Codelivered Antigens

Journal of Virology ◽

10.1128/jvi.00394-09 ◽

2009 ◽

Vol 83 (21) ◽

pp. 10941-10950 ◽

Cited By ~ 10

Author(s):

Avi-Hai Hovav ◽

Michael Santosuosso ◽

Maytal Bivas-Benita ◽

Andre Plair ◽

Alex Cheng ◽

...

Keyword(s):

Immune Response ◽

Human Immunodeficiency Virus ◽

Antigen Presentation ◽

Antigen Expression ◽

V3 Loop ◽

Humoral Immune ◽

Immunodeficiency Virus ◽

Aids Vaccines ◽

Hiv 1

ABSTRACT In order to increase the immune breadth of human immunodeficiency virus (HIV) vaccines, strategies such as immunization with several HIV antigens or centralized immunogens have been examined. HIV-1 gp120 protein is a major immunogen of HIV and has been routinely considered for inclusion in both present and future AIDS vaccines. However, recent studies proposed that gp120 interferes with the generation of immune response to codelivered antigens. Here, we investigate whether coimmunization with plasmid-encoded gp120 alters the immune response to other coadministered plasmid encoded antigens such as luciferase or ovalbumin in a mouse model. We found that the presence of gp120 leads to a significant reduction in the expression level of the codelivered antigen in vivo. Antigen presentation by antigen-presenting cells was also reduced and resulted in the induction of weak antigen-specific cellular and humoral immune responses. Importantly, gp120-mediated immune interference was observed after administration of the plasmids at the same or at distinct locations. To characterize the region in gp120 mediating these effects, we used plasmid constructs encoding gp120 that lacks the V1V2 loops (ΔV1V2) or the V3 loop (ΔV3). After immunization, the ΔV1V2, but not the ΔV3 construct, was able to reduce antigen expression, antigen presentation, and subsequently the immunogenicity of the codelivered antigen. The V3 loop dependence of this phenomenon seems to be limited to V3 loops known to interact with the CXCR4 molecule but not with CCR5. Our study presents a novel mechanism by which HIV-1 gp120 interferes with the immune response against coadministered antigen in a polyvalent vaccine preparation.

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Structural requirements for and consequences of an antiviral porphyrin binding to the V3 loop of the human immunodeficiency virus (HIV-1) envelope glycoprotein gp120

Journal of Molecular Recognition ◽

10.1002/jmr.300080604 ◽

1995 ◽

Vol 8 (6) ◽

pp. 345-357 ◽

Cited By ~ 20

Author(s):

A. Robert Neurath ◽

Nathan Strick ◽

Asim K. Debnath

Keyword(s):

Human Immunodeficiency Virus ◽

Envelope Glycoprotein ◽

V3 Loop ◽

Structural Requirements ◽

Envelope Glycoprotein Gp120 ◽

Immunodeficiency Virus ◽

Glycoprotein Gp120 ◽

Hiv 1

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Betulinic Acid Derivatives That Target gp120 and Inhibit Multiple Genetic Subtypes of Human Immunodeficiency Virus Type 1

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00737-07 ◽

2007 ◽

Vol 52 (1) ◽

pp. 128-136 ◽

Cited By ~ 27

Author(s):

Weihong Lai ◽

Li Huang ◽

Phong Ho ◽

Zhijun Li ◽

David Montefiori ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Broad Spectrum ◽

Betulinic Acid ◽

V3 Loop ◽

Entry Inhibitors ◽

Immunodeficiency Virus ◽

Anti Hiv ◽

Hiv 1

ABSTRACT Betulinic acid (BA) derivatives can inhibit human immunodeficiency virus type 1 (HIV-1) entry or maturation depending on side chain modifications. While BA derivatives with antimaturation activity have attracted considerable interest, the anti-HIV-1 profile and molecular mechanism of BA derivatives with anti-HIV-1 entry activity (termed BA entry inhibitors) have not been well defined. In this study, we have found that two BA entry inhibitors, IC9564 and A43D, exhibited a broad spectrum of anti-HIV-1 activity. Both compounds inhibited multiple strains of HIV-1 from clades A, B, and C at submicromolar concentrations. Clade C viruses were more sensitive to the compounds than clade A and B viruses. Interestingly, IC9564 at subinhibitory concentrations could alter the antifusion activities of other entry inhibitors. IC9564 was especially potent in increasing the sensitivity of HIV-1YU2 Env-mediated membrane fusion to the CCR5 inhibitor TAK-779. Results from this study suggest that the V3 loop of gp120 is a critical determinant for the anti-HIV-1 activity of IC9564. IC9564 escape viruses contained mutations near the tip of the V3 loop. Moreover, IC9564 could compete with the binding of V3 monoclonal antibodies 447-52D and 39F. IC9564 also competed with the binding of gp120/CD4 complexes to chemokine receptors. In summary, these results suggest that BA entry inhibitors can potently inhibit a broad spectrum of primary HIV-1 isolates by targeting the V3 loop of gp120.

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Enhancement of human immunodeficiency virus type 1 infection by antisera to peptides from the envelope glycoproteins gp120/gp41.

Journal of Experimental Medicine ◽

10.1084/jem.174.6.1557 ◽

1991 ◽

Vol 174 (6) ◽

pp. 1557-1563 ◽

Cited By ~ 62

Author(s):

S B Jiang ◽

K Lin ◽

A R Neurath

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Neutralizing Antibodies ◽

Rational Design ◽

Envelope Glycoproteins ◽

V3 Loop ◽

Immunodeficiency Virus ◽

Hiv 1

Human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (gp120 and gp41) elicit virus-neutralizing antibodies (VNAB) and also antibodies enhancing HIV-1 infection (EAB). Several epitopes eliciting VNAB have been defined, the principal virus-neutralizing determinant being assigned to the V3 loop of gp120. To provide a background for a rational design of anti-HIV vaccines, it also appears important to define domains eliciting EAB. This was accomplished by screening antisera against synthetic peptides covering almost the entire sequence of gp120/gp41 for their enhancing effects on HIV-1 infection of MT-2 cells, a continuous T cell line. Many (16/30) of the antisera significantly enhanced HIV-1 in the presence of human complement. Antibodies to complement receptor type 2 (CR2) abrogated the antibody-mediated enhancement of HIV-1 infection. Antisera to V3 hypervariable loops of 21 distinct HIV-1 isolates were also tested for their enhancing effects on HIV-1IIIB infection. 11 of these sera contained VNAB and 10 enhanced HIV-1IIIB infection. All antisera with virus-enhancing activity contained antibodies crossreactive with the V3 loop of HIV-1IIIB, and the virus-enhancing activity increased with increasing serological crossreactivity. These results suggest that immunization with antigens encompassing V3 loops may elicit EAB rather than protective antibodies if epitopes on the immunogen and the predominant HIV-1 isolate infecting a population are insufficiently matched, i.e., crossreactive serologically but not at the level of virus neutralization.

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Human immunodeficiency virus type 1 neutralization is determined by epitope exposure on the gp120 oligomer.

Journal of Experimental Medicine ◽

10.1084/jem.182.1.185 ◽

1995 ◽

Vol 182 (1) ◽

pp. 185-196 ◽

Cited By ~ 267

Author(s):

Q J Sattentau ◽

J P Moore

Keyword(s):

Human Immunodeficiency Virus ◽

Cell Line ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Virus Neutralization ◽

V3 Loop ◽

Immunodeficiency Virus ◽

Monomeric Gp120 ◽

Hiv 1

The major target of the neutralizing antibody response to infection by the human immunodeficiency virus type 1 (HIV-1) is the outer envelope glycoprotein, gp120. The spectrum of HIV-1 neutralization specificity is currently represented by monoclonal antibodies (mAbs) that can be divided broadly into five groups. We have studied the binding of these mAbs to functional oligomeric and soluble monomeric gp120 derived from the molecular clone of a cell line-adapted isolate of HIV-1, and compared these binding properties with virus neutralization. Binding of all mAbs except those reactive with the V3 loop was much weaker to oligomeric than to monomeric gp120. This reduction in binding to oligomeric gp120 was determined mostly by a slower relative rate of association, although the dissociation rate also had some influence on relative variation in mAb affinity. Virus neutralization correlated broadly with mAb binding to the oligomeric rather than to the monomeric form of gp120, and neutralization potency was related to the estimated association rate. Thus, with the exception of the hypervariable V3 loop, regions of HIV-1 gp120 with the potential to induce a neutralization response are likely to be poorly presented for antibody recognition on the surface of cell line-adapted virions.

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A Single Injection of Recombinant Measles Virus Vaccines Expressing Human Immunodeficiency Virus (HIV) Type 1 Clade B Envelope Glycoproteins Induces Neutralizing Antibodies and Cellular Immune Responses to HIV

Journal of Virology ◽

10.1128/jvi.78.1.146-157.2004 ◽

2004 ◽

Vol 78 (1) ◽

pp. 146-157 ◽

Cited By ~ 97

Author(s):

Clarisse Lorin ◽

Lucile Mollet ◽

Frédéric Delebecque ◽

Chantal Combredet ◽

Bruno Hurtrel ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Immune Responses ◽

Neutralizing Antibodies ◽

Measles Virus ◽

Single Injection ◽

Protein A ◽

V3 Loop ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT The anchored and secreted forms of the human immunodeficiency virus type 1 (HIV-1) 89.6 envelope glycoprotein, either complete or after deletion of the V3 loop, were expressed in a cloned attenuated measles virus (MV) vector. The recombinant viruses grew as efficiently as the parental virus and expressed high levels of the HIV protein. Expression was stable during serial passages. The immunogenicity of these recombinant vectors was tested in mice susceptible to MV and in macaques. High titers of antibodies to both MV and HIV-Env were obtained after a single injection in susceptible mice. These antibodies neutralized homologous SHIV89.6p virus, as well as several heterologous HIV-1 primary isolates. A gp160 mutant in which the V3 loop was deleted induced antibodies that neutralized heterologous viruses more efficiently than antibodies induced by the native envelope protein. A high level of CD8+ and CD4+ cells specific for HIV gp120 was also detected in MV-susceptible mice. Furthermore, recombinant MV was able to raise immune responses against HIV in mice and macaques with a preexisting anti-MV immunity. Therefore, recombinant MV vaccines inducing anti-HIV neutralizing antibodies and specific T lymphocytes responses deserve to be tested as a candidate AIDS vaccine.

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Changes in the Immunogenic Properties of Soluble gp140 Human Immunodeficiency Virus Envelope Constructs upon Partial Deletion of the Second Hypervariable Region

Journal of Virology ◽

10.1128/jvi.77.4.2310-2320.2003 ◽

2003 ◽

Vol 77 (4) ◽

pp. 2310-2320 ◽

Cited By ~ 92

Author(s):

Indresh K. Srivastava ◽

Keating VanDorsten ◽

Lucia Vojtech ◽

Susan W. Barnett ◽

Leonidas Stamatatos

Keyword(s):

Human Immunodeficiency Virus ◽

Binding Site ◽

Hypervariable Region ◽

V3 Loop ◽

Virus Envelope ◽

Immunodeficiency Virus ◽

Cd4 Binding Site ◽

Hiv Envelope ◽

Immunogenic Properties ◽

Hiv 1

ABSTRACT Immunization of macaques with the soluble oligomeric gp140 form of the SF162 envelope (SF162gp140) or with an SF162gp140-derived construct lacking the central region of the V2 loop (ΔV2gp140) results in the generation of high titers of antibodies capable of neutralizing the homologous human immunodeficiency virus type 1 (HIV-1), SF162 virus (Barnett et al. J. Virol. 75 :5526-5540, 2001). However, the ΔV2gp140 immunogen is more effective than the SF162gp140 immunogen in eliciting the generation of antibodies capable of neutralizing heterologous HIV-1 isolates. This indicates that deletion of the V2 loop alters the immunogenicity of the SF162gp140 protein. The present studies were aimed at identifying the envelope regions whose immunogenicity is altered following V2 loop deletion. We report that the antibodies elicited by the SF162gp140 immunogen recognize elements of the V1, V2, and V3 loops, the CD4-binding site, and the C1 and C2 regions on the homologous SF162 gp120. With the exception of the V1 and V2 loops, the same regions are recognized on heterologous gp120 proteins. Surprisingly, although a minority of the SF162gp140-elicited antibodies target the V3 loop on the homologous gp120, the majority of the antibodies elicited by this immunogen that are capable of binding to the heterologous gp120s tested recognize their V3 loops. Deletion of the V2 loop has two effects. First, it alters the immunogenicity of the V3 and V1 loops, and second, it renders the C5 region immunogenic. Although deletion of the V2 loop does not result in an increase in the immunogenicity of the CD4-binding site per se, the relative ratio of anti-CD4-binding site to anti-V3 loop antibodies that bind to the heterologous gp120s tested is higher in sera collected from the ΔV2gp140-immunized animals than in the SF162gp140-immunized animals. Overall, our studies indicate that it is possible to alter the immunogenic structure of the HIV envelope by introducing specific modifications.

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Anti-Human Immunodeficiency Virus Type 1 Activity of R-95288, a Phosphodiester Hexadeoxyribonucleotide Modified by Dibenzyloxybenzyl and Hydroxyethyl Residues at the 5′- and 3′-Ends

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029700800505 ◽

1997 ◽

Vol 8 (5) ◽

pp. 429-438 ◽

Cited By ~ 4

Author(s):

T Agatsuma ◽

H Furukawa ◽

H Hotoda ◽

M Koizumi ◽

R Koga ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Specific Interaction ◽

V3 Loop ◽

Virus Envelope ◽

Immunodeficiency Virus ◽

Hiv 1

The phosphodiester hexadeoxyribonucleotide R-95288 is a potent anti-human immunodeficiency virus type 1 (HIV-1) agent in vitro which consists or a TGGGAG nucleoside sequence with dibenzyloxybenzyl and hydroxyethyl substituents at the 5′- and 3′-ends, respectively. In this study, the antiviral activity of R-95288 against various strains of HIV-1 in vitro was assessed and its mechanism of action was analysed. R-95288 inhibited replication of all strains of HIV-1 used including laboratory strains with the syncytium-inducing (SI) phenotype and clinical isolates with both SI and non-SI (NSI) phenotypes. The 50% inhibitory concentrations (IC50s) were 0.62–18 μg mL−1 (0.21–6.2 μM). R-95288 inhibited the binding and fusion of HIV-1-infected T cells with CD4+ cells. In addition, R-95288 specifically blocked the binding of monoclonal antibodies, recognizing the anti-V3 loop or the CD4-binding site of the virus envelope glycoprotein gp120. Furthermore, the target site of R-95288 within the V3 loop was found in the putative heparin-binding region by binding inhibition assays using various anti-V3 loop antibodies. These results suggest that R-95288 can inhibit various strains of HIV-1, possibly by specific interaction with gp120.

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