Complementary and synergistic activities of anti-V3, CD4bs and CD4i antibodies derived from a single individual can cover a wide range of HIV-1 strains

Valdez, Kristel Paola Ramirez; Kuwata, Takeo; Maruta, Yasuhiro; Tanaka, Kazuki; Alam, Muntasir; Yoshimura, Kazuhisa; Matsushita, Shuzo

doi:10.1016/j.virol.2014.11.011

Cited by 23 publications

(37 citation statements)

References 115 publications

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“…A similarly low percentage of somatic hypermutations in the VH, mean 7.9%, was observed in another study of 25 neutralizing mAbs against V3, CD4bs and CD4-induced epitopes which were isolated from one chronically HIV-1 infected individual (Ramirez Valdez et al, 2014). However, only a moderate correlation between the percentage of mutations and neutralization of tier 2, 3, but not tier 1 viruses, was determined.…”

Section: Discussionsupporting

confidence: 63%

A broad range of mutations in HIV-1 neutralizing human monoclonal antibodies specific for V2, V3, and the CD4 binding site

Wang

Williams

et al. 2015

Molecular Immunology

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The HIV vaccine-induced neutralizing antibodies (Abs) display low rates of mutation in their variable regions. To determine the range of neutralization mediated by similar human monoclonal Abs (mAbs) but derived from unselected chronically HIV-1 infected subjects, we tested a panel of 66 mAbs specific to V3, CD4 binding site (CD4bs) and V2 regions. The mAbs were tested against 41 pseudoviruses, including 15 tier 1 and 26 tier 2, 3 viruses, showing that the neutralization potency and breadth of anti-V3 mAbs were significantly higher than those of the anti-CD4bs and anti-V2 mAbs, and only anti-V3 mAbs were able to neutralize some tier 2, 3 viruses. The percentage of mutations in the variable regions of the heavy (VH) and light (VL) chains varied broadly in a range from 2% to 18% and correlated moderately with the neutralization breadth of tier 2, 3 viruses. There was no correlation with neutralization of tier 1 viruses as some mAbs with low and high percentages of mutations neutralized the same number of viruses. The electrostatic interactions between anti-V3 mAbs and the charged V3 region may contribute to their neutralization because the isoelectric points of the VH CDR3 of 48 anti-V3 mAbs were inversely correlated with the neutralization breadth of tier 2, 3 viruses. The results demonstrate that infection-induced antibodies to CD4bs, V3 and V2 regions can mediate cross-clade neutralization despite low levels of mutations which can be achieved by HIV-1 vaccine-induced antibodies.

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Section: Discussionsupporting

confidence: 63%

A broad range of mutations in HIV-1 neutralizing human monoclonal antibodies specific for V2, V3, and the CD4 binding site

Wang

Williams

et al. 2015

Molecular Immunology

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“…4B). This is supported by the finding that an arginine-to-lysine substitution at position 315 in the V3 region of Env in the 0.5␥ epitope (47) correlates with the 0.5␥ resistance of two KK 652-67/0.5␥-7 clones, clones 89 and 93 (Fig. 5A).…”

Section: Figmentioning

confidence: 53%

“…These so-called conventional antibodies have limited breadth and potency and are commonly induced in HIV-1-infected patients, as described previously (47). In addition, the monoclonal NAbs VRC01 and 10E8, which recognize CD4bs and the gp41 membrane-proximal external region (MPER), respectively, were used as representatives of the broadly NAbs.…”

Section: Figmentioning

confidence: 99%

Incompatible Natures of the HIV-1 Envelope in Resistance to the CCR5 Antagonist Cenicriviroc and to Neutralizing Antibodies

Kuwata

Enomoto

Baba

et al. 2016

Antimicrob Agents Chemother

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bCenicriviroc is a CCR5 antagonist which prevents human immunodeficiency virus type 1 (HIV-1) from cellular entry. The CCR5-binding regions of the HIV-1 envelope glycoprotein are important targets for neutralizing antibodies (NAbs), and mutations conferring cenicriviroc resistance may therefore affect sensitivity to NAbs. Here, we used the in vitro induction of HIV-1 variants resistant to cenicriviroc or NAbs to examine the relationship between resistance to cenicriviroc and resistance to NAbs. The cenicriviroc-resistant variant KK 652-67 (strain KK passaged 67 times in the presence of increasing concentrations of cenicriviroc) was sensitive to neutralization by NAbs against the V3 loop, the CD4-induced (CD4i) region, and the CD4-binding site (CD4bs), whereas the wild-type (WT) parental HIV-1 strain KK WT from which cenicriviroc-resistant strain KK 652-67 was obtained was resistant to these NAbs. The V3 region of KK 652-67 was important for cenicriviroc resistance and critical to the high sensitivity of the V3, CD4i, and CD4bs epitopes to NAbs. Moreover, induction of variants resistant to anti-V3 NAb 0.5␥ and anti-CD4i NAb 4E9C from cenicriviroc-resistant strain KK 652-67 resulted in reversion to the cenicriviroc-sensitive phenotype comparable to that of the parental strain, KK WT . Resistance to 0.5␥ and 4E9C was caused by the novel substitutions R315K, G324R, and E381K in the V3 and C3 regions near the substitutions conferring cenicriviroc resistance. Importantly, these amino acid changes in the CCR5-binding region were also responsible for reversion to the cenicriviroc-sensitive phenotype. These results suggest the presence of key amino acid residues where resistance to cenicriviroc is incompatible with resistance to NAbs. This implies that cenicriviroc and neutralizing antibodies may restrict the emergence of variants resistant to each other.

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“…Plasma samples from HIV-1-infected patients, including patient KTS376 described in our previous study, were collected and purified using protein A-Sepharose (Affi-gel Protein A; Bio-Rad, Hercules, CA, USA) [ 26 ].…”

Section: Methodsmentioning

confidence: 99%

Enhanced antibody-mediated neutralization of HIV-1 variants that are resistant to fusion inhibitors

et al. 2016

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BackgroundHIV-1 typically develops resistance to any single antiretroviral agent. Combined anti-retroviral therapy to reduce drug-resistance development is necessary to control HIV-1 infection. Here, to assess the utility of a combination of antibody and fusion inhibitor treatments, we investigated the potency of monoclonal antibodies at neutralizing HIV-1 variants that are resistant to fusion inhibitors.ResultsMutations that confer resistance to four fusion inhibitors, enfuvirtide, C34, SC34, and SC34EK, were introduced into the envelope of HIV-1JR-FL, a CCR5-tropic tier 2 strain. Pseudoviruses with these mutations were prepared and used for the assessment of neutralization sensitivity to an array of antibodies. The resulting neutralization data indicate that the potencies of some antibodies, especially of those against the CD4 binding site, V3 loop, and membrane-proximal external region epitopes, were increased by the mutations in gp41 that conferred resistance to the fusion inhibitors. C34-, SC34-, and SC34EK-resistant mutants showed more sensitivity to monoclonal antibodies than enfuvirtide-resistant mutants. An analysis of C34-resistant mutations revealed that the I37K mutation in gp41 HR1 is a key mutation for C34 resistance, low infectivity, neutralization sensitivity, epitope exposure, and slow fusion kinetics. The N126K mutation in the gp41 HR2 domain contributed to C34 resistance and neutralization sensitivity to anti-CD4 binding site antibodies. In the absence of L204I, the effect of N126K was antagonistic to that of I37K. The results of a molecular dynamic simulation of the envelope trimer confirmation suggest that an I37K mutation induces the augmentation of structural fluctuations prominently in the interface between gp41 and gp120. Our observations indicate that the “conformational unmasking” of envelope glycoprotein by an I37K mutation is one of the mechanisms of neutralization sensitivity enhancement. Furthermore, the enhanced neutralization of C34-resistant mutants in vivo was shown by its high rate of neutralization by IgG from HIV patient samples.ConclusionsMutations in gp41 that confer fusion inhibitor resistance exert enhanced sensitivity to broad neutralizing antibodies (e.g., VRC01 and 10E8) and other conventional antibodies developed in HIV-1 infected patients. Therefore, next-generation fusion inhibitors and monoclonal antibodies could be a potential combination for future regimens of combined antiretroviral therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-016-0304-7) contains supplementary material, which is available to authorized users.

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Complementary and synergistic activities of anti-V3, CD4bs and CD4i antibodies derived from a single individual can cover a wide range of HIV-1 strains

Cited by 23 publications

References 115 publications

A broad range of mutations in HIV-1 neutralizing human monoclonal antibodies specific for V2, V3, and the CD4 binding site

A broad range of mutations in HIV-1 neutralizing human monoclonal antibodies specific for V2, V3, and the CD4 binding site

Incompatible Natures of the HIV-1 Envelope in Resistance to the CCR5 Antagonist Cenicriviroc and to Neutralizing Antibodies

Enhanced antibody-mediated neutralization of HIV-1 variants that are resistant to fusion inhibitors

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