Rabbit Anti-HIV-1 Monoclonal Antibodies Raised by Immunization Can Mimic the Antigen-Binding Modes of Antibodies Derived from HIV-1-Infected Humans

Pan, Ruimin; Sampson, Jared M.; Chen, Yuxin; Vaine, Michael; Wang, Shixia; Lu, Shan; Kong, Xiang‐Peng

doi:10.1128/jvi.00843-13

Cited by 38 publications

(38 citation statements)

References 61 publications

(93 reference statements)

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“…The orthologue of the human VH5-51 gene segment in rhesus macaques is VH5.7, used by one of our V3-specific MAbs, GE2.JF11. Studies of V3-directed MAbs elicited in Env-immunized rabbits resulted in the isolation of the R56 MAb, which binds by the cradle mode via an epitope that overlaps with peptide 5 identified as the target epitope in our current study (31, 65). R56 was shown to neutralize a similar set of viruses as the V3-specific rhesus MAbs isolated here, suggesting that the V3-specific MAbs identified in our study bind by a similar mode of recognition.…”

Section: Discussionmentioning

confidence: 76%

Diverse Antibody Genetic and Recognition Properties Revealed following HIV-1 Envelope Glycoprotein Immunization

Phad

Bernat

Feng

et al. 2015

The Journal of Immunology

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Isolation of monoclonal antibodies (MAbs) elicited by vaccination provides opportunities to define the development of effective immunity. Ab responses elicited by current HIV-1 envelope glycoprotein (Env) immunogens display narrow neutralizing activity with limited capacity to block infection by tier 2 viruses. Intense work in the field suggests that improved Env immunogens are forthcoming and it is therefore important to concurrently develop approaches to investigate the quality of vaccine-elicited responses at a higher level of resolution. Here, we cloned a representative set of MAbs elicited by a model Env immunogen in rhesus macaques and comprehensively characterized their genetic and functional properties. The MAbs were genetically diverse, even within groups of Abs targeting the same sub-region of Env, consistent with a highly polyclonal response. MAbs directed against two sub-determinants of Env, the CD4 binding site (CD4bs) and the V3 region, could in part account for the neutralizing activity observed in the plasma of the animal from which they were cloned, demonstrating the power of MAb isolation for a detailed understanding of the elicited response. Finally, through comparative analyses of MAb binding and neutralizing capacity of HIV-1 using matched Envs, we demonstrate complex relationships between epitope recognition and accessibility, highlighting the protective quaternary packing of the HIV-1 spike relative to vaccine-induced MAbs.

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Section: Discussionmentioning

confidence: 76%

Diverse Antibody Genetic and Recognition Properties Revealed following HIV-1 Envelope Glycoprotein Immunization

Phad

Bernat

Feng

et al. 2015

The Journal of Immunology

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“…The different groups of rabbits receiving clade C Env immunogens also produced primarily the V3C-type Abs. A recent study reported that one of the two anti-V3 crown mAbs isolated from a rabbit immunized with the HIV Env gp120 JRFL (clade B) using a DNA prime-protein boost regimen binds to its epitope in a V3C-binding mode [23]. The frequencies of V3L responders are also unlikely determined by the GPGR motif typically present in clade B Envs [38] .…”

Section: Discussionmentioning

confidence: 99%

Differential induction of anti-V3 crown antibodies with cradle- and ladle-binding modes in response to HIV-1 envelope vaccination

Balasubramanian

Kumar

Williams

et al. 2017

Vaccine

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The V3 loop in the HIV envelope gp120 is one of the immunogenic sites targeted by Abs. The V3 crown in particular has conserved structural elements recognized by cross-reactive neutralizing Abs, indicating its potential contribution in protection against HIV. Crystallographic analyses of anti-V3 crown mAbs in complex with the V3 peptides have revealed that these mAbs recognize the conserved sites on the V3 crown via two distinct strategies: a cradle-binding mode (V3C) and a ladle-binding (V3L) mode. However, almost all of the anti-V3 crown mAbs studied in the past were isolated from chronically HIV-infected individuals. The extents to which the two types of anti-V3 crown Abs are generated by vaccination are unknown. This study analyzed the prevalence of V3C-type and V3L-type Ab responses in HIV-infected individuals and in HIV envelope-immunized humans and animals using peptide mimotopes that distinguish the two Ab types. The results show that both V3L-type and V3C-type Abs were generated by the vast majority of chronically HIV-infected humans, although the V3L-type were more prevalent. In contrast, only one of the two V3 Ab types was elicited in vaccinated humans or animal models, irrespective of HIV-1 envelope clades, envelope constructs (oligomeric or monomeric), and protocols (DNA plus protein or protein alone) used for vaccinations. The V3C-type Abs were produced by vaccinated humans, macaques, and rabbits, whereas the V3L-type Abs were made by mice. The V3C-type and V3L-type Abs generated by the vaccinations were able to mediate virus neutralization. These data indicate the restricted repertoires and the species-specific differences in the functional V3-specific Ab responses induced by the HIV envelope vaccines. The study implies the need for improving immunogen designs and vaccination strategies to broaden the diversity of Abs in order to target the different conserved epitopes in the V3 loop and, by extension, in the entire HIV envelope.

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“…S6A). Rabbits may be preferable as small animal models (Pan et al, 2013; Pinheiro et al, 2011) because they lack this serum background problem and also react better with conserved targets that may ultimately be important for the development of nAbs of any breadth. However, it is important to point out that the VH family diversity in both rabbits and guinea pigs is quite limited compared to primates and that their antibody diversity is generated principally by gene conversion, contrasting with the largely combinatorial origins of IgG diversity in primates (somatic hypermutation is also used in all cases).…”

Section: Discussionmentioning

confidence: 99%

Multi-parameter exploration of HIV-1 virus-like particles as neutralizing antibody immunogens in guinea pigs, rabbits and macaques

et al. 2014

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Virus-like particles (VLPs) offer a platform to test the hypothesis that, since antibody binding to native envelope glycoprotein (Env) trimers results in HIV-1 neutralization, that native Env trimers presented in membranes may be useful for inducing neutralizing antibodies (nAbs) in a vaccine setting. So far, VLPs have not fulfilled this potential. Here, using a “shotgun” approach, we evaluated a wide cross-section of variables in a series of VLP immunizations. We identified 3 tentative leads. First, that VLP doses may not have been sufficient for optimal nAb induction. Second, that dampening the antigenicity of non-functional Env (for example uncleaved gp160) using either protease digests or IgG masking may be useful. Third, that guinea pig sera preferentially target non-conserved epitopes and exhibit relatively high background activity, suggesting that rabbits may be preferable as small animal vaccine models. Recent immunogenicity studies in rabbits appear to bear out all 3 of these leads.

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Rabbit Anti-HIV-1 Monoclonal Antibodies Raised by Immunization Can Mimic the Antigen-Binding Modes of Antibodies Derived from HIV-1-Infected Humans

Cited by 38 publications

References 61 publications

Diverse Antibody Genetic and Recognition Properties Revealed following HIV-1 Envelope Glycoprotein Immunization

Diverse Antibody Genetic and Recognition Properties Revealed following HIV-1 Envelope Glycoprotein Immunization

Differential induction of anti-V3 crown antibodies with cradle- and ladle-binding modes in response to HIV-1 envelope vaccination

Multi-parameter exploration of HIV-1 virus-like particles as neutralizing antibody immunogens in guinea pigs, rabbits and macaques

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