Anti-gp41 Antibodies Cloned from HIV-Infected Patients with Broadly Neutralizing Serologic Activity

Pietzsch, John; Scheid, Johannes F.; Mouquet, Hugo; Seaman, Michael S.; Broder, Christopher C.; Nussenzweig, Michel C.

doi:10.1128/jvi.00154-10

Cited by 55 publications

(52 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our study indicates that gp140-elicited gp41 antibodies (at least those directed to the MPER) are nonneutralizing. We acknowledge the possibility that anti-gp41 Abs outside the MPER, which were not accounted for in our HIV-2/1 MPER chimera assay, may have contributed to neutralization (14,37). D368R gp120 competitions.…”

Section: Vol 84 2010 Effect Of V1 On Hiv Env Immunogenicity 9941mentioning

confidence: 99%

Alterations in the Immunogenic Properties of Soluble Trimeric Human Immunodeficiency Virus Type 1 Envelope Proteins Induced by Deletion or Heterologous Substitutions of the V1 Loop

Ching

Stamatatos

2010

J Virol

View full text Add to dashboard Cite

HIV-1 gp140 envelope immunogens express conserved epitopes that are targeted by broadly cross-reactive neutralizing antibodies, but they fail to elicit similar antibodies upon immunization. The poor immunogenicity of conserved epitopes on gp140 could be linked to the high immunogenicity of variable Env regions on such constructs. Previous studies have shown that the first hypervariable region (V1 loop) is immunogenic on soluble gp140s but elicits type-specific antibodies. To address issues related to the high immunogenicity of the V1 loop, two conceptually opposite approaches were tested. In the first approach, we eliminated the V1 loop from our gp140 construct and examined how V1 deletion altered the immunogenic properties of other Env regions. In the second approach, we took advantage of the high immunogenicity of the V1 loop and engrafted four diverse V1 loops onto a common gp140 Env "scaffold." These four scaffolds were used as a cocktail of immunogens to elicit diverse anti-V1 antibodies, under the hypothesis that eliciting diverse anti-V1 antibodies would expand the neutralizing breadth of immune sera. Our study indicates that three of four heterologous V1 loops were immunogenic on the common Env backbone "scaffold," but heterologous anti-V1 neutralizing responses were observed in only one case. Both types of V1 modification dampened the immunogenicity of the V3 loop, differentially altered the immunogenicity of the transmembrane gp41 subunit, and altered the relative immunogenicities of unknown Env regions, including potentially the CD4-binding site (CD4-bs) and trimerspecific targets, which elicited cross-reactive neutralizing antibodies but of limited breadth.An effective vaccine against human immunodeficiency virus type 1 (HIV-1) will need to incorporate an envelope-derived immunogen capable of eliciting potent and broadly cross-reactive neutralizing antibody responses against diverse primary HIV-1 isolates. The target of anti-HIV neutralizing antibodies (NAbs), the viral envelope (Env) glycoprotein, is expressed as a single transmembrane polypeptide precursor (gp160) that is glycosylated and cleaved into an extracellular subunit (gp120) and a transmembrane subunit (gp41) during intracellular processing (10,20,21,54). The functional Env form on virion surfaces is a trimer composed of three noncovalently associated gp120-gp41 heterodimers. Soluble forms of the trimeric Env have been generated by introducing stop codons immediately upstream of the transmembrane domain of gp41. These constructs are commonly referred to as gp140 proteins and have been tested extensively as immunogens to elicit anti-HIV-1 NAbs. Soluble gp140s express epitopes that are targets of NAbs, including cross-reactive NAbs such as b12, 4E10, and 2G12 (5,17,34,45,47,49,50,52,57). Immunization with gp140 immunogens nonetheless does not result in a broadly cross-reactive neutralizing antibody response (2,3,17,18,26,56,58).Epitope mapping analyses of the Abs elicited by soluble trimeric gp140 immunogens revealed that a large fraction of...

show abstract

Section: Vol 84 2010 Effect Of V1 On Hiv Env Immunogenicity 9941mentioning

confidence: 99%

Alterations in the Immunogenic Properties of Soluble Trimeric Human Immunodeficiency Virus Type 1 Envelope Proteins Induced by Deletion or Heterologous Substitutions of the V1 Loop

Ching

Stamatatos

2010

J Virol

View full text Add to dashboard Cite

show abstract

“…Antibody 10-188 binds to a linear epitope in the variable loop V3 (gp120 V3 ) (59), and the other two anti-gp120 antibodies recognize conformational epitopes in the CD4 binding site (CD4bs) and CD4-induced coreceptor binding site (CD4i) (1-863 and 4-42, respectively) (Table S1) (60). Anti-gp120 antibodies were paired with anti-gp41 antibody 5-25, which is directed against the immunodominant linear epitope of gp41 (gp41 ID ) (63) (Fig. S2 A and B) or with the nonspecific mGO53 control (61).…”

Section: Bivalent Scfv-fc Recapitulates Binding and Neutralizing Propmentioning

confidence: 99%

Enhanced HIV-1 neutralization by antibody heteroligation

Mouquet

Warncke

Scheid

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Passive transfer of broadly neutralizing human antibodies against HIV-1 protects macaques against infection. However, HIV-1 uses several strategies to escape antibody neutralization, including mutation of the gp160 viral surface spike, a glycan shield to block antibody access to the spike, and expression of a limited number of viral surface spikes, which interferes with bivalent antibody binding. The latter is thought to decrease antibody apparent affinity or avidity, thereby interfering with neutralizing activity. To test the idea that increasing apparent affinity might enhance neutralizing activity, we engineered bispecific anti–HIV-1 antibodies (BiAbs) that can bind bivalently by virtue of one scFv arm that binds to gp120 and a second arm to the gp41 subunit of gp160. The individual arms of the BiAbs preserved the binding specificities of the original anti-HIV IgG antibodies and together bound simultaneously to gp120 and gp41. Heterotypic bivalent binding enhanced neutralization compared with the parental antibodies. We conclude that antibody recognition and viral neutralization of HIV can be improved by heteroligation.

show abstract

“…Alternative explanations for the rarity of MPER antibodies may include the immunodominance of the gp120 variable loops (38), the rapidity of conformational changes that expose the MPER (39), masking by nonneutralizing cluster II epitopes (40), or a bias in the germ line antibody repertoire (41). However, responses from B-cell clones against gp41 are distributed across clusters I, II, and IV, suggesting that epitope masking is not the cause for failure to neutralize the virus (42).…”

mentioning

confidence: 99%

Rational Design of Membrane Proximal External Region Lipopeptides Containing Chemical Modifications for HIV-1 Vaccination

Venditto

Watson

Motion

et al. 2013

Clin Vaccine Immunol

View full text Add to dashboard Cite

The inability to generate broadly neutralizing antibody (bnAb) responses to the membrane proximal external region (MPER) of HIV-1 gp41 using current vaccine strategies has hampered efforts to prevent the spread of HIV. To address this challenge, we investigated a novel hypothesis to help improve the anti-MPER antibody response. Guided by structural insights and the unique lipid reactivity of anti-MPER bnAbs, we considered whether amino acid side chain modifications that emulate hydrophilic phospholipid head groups could contribute to the generation of 2F5-like or 4E10-like neutralizing anti-MPER antibodies. To test this hypothesis, we generated a series of chemically modified MPER immunogens through derivatization of amino acid side chains with phosphate or nitrate groups. We evaluated the binding affinity of the chemically modified peptides to their cognate monoclonal antibodies, 2F5 and 4E10, using surface plasmon resonance. The modifications had little effect on binding to the antibodies and did not influence epitope secondary structure when presented in liposomes. We selected five of the chemically modified sequences to immunize rabbits and found that an immunogen containing both the 2F5 and 4E10 epitopes and a phosphorylated threonine at T676 elicited the highest anti-peptide IgG titers, although the high antipeptide titers did not confer higher neutralizing activity. These data indicate that side chain modifications adjacent to known neutralizing antibody epitopes are capable of eliciting antibody responses to the MPER but that these chemically modified gp41 epitopes do not induce neutralizing antibodies.

show abstract

Anti-gp41 Antibodies Cloned from HIV-Infected Patients with Broadly Neutralizing Serologic Activity

Cited by 55 publications

References 62 publications

Alterations in the Immunogenic Properties of Soluble Trimeric Human Immunodeficiency Virus Type 1 Envelope Proteins Induced by Deletion or Heterologous Substitutions of the V1 Loop

Alterations in the Immunogenic Properties of Soluble Trimeric Human Immunodeficiency Virus Type 1 Envelope Proteins Induced by Deletion or Heterologous Substitutions of the V1 Loop

Enhanced HIV-1 neutralization by antibody heteroligation

Rational Design of Membrane Proximal External Region Lipopeptides Containing Chemical Modifications for HIV-1 Vaccination

Contact Info

Product

Resources

About