scholarly journals Functional Homology for Antibody-Dependent Phagocytosis Across Humans and Rhesus Macaques

2021 ◽  
Vol 12 ◽  
Author(s):  
Justin Pollara ◽  
Matthew Zirui Tay ◽  
R. Whitney Edwards ◽  
Derrick Goodman ◽  
Andrew R. Crowley ◽  
...  
Keyword(s):  
Rhesus Macaques ◽  
Passive Immunization ◽  
Virus Challenge ◽  
Vaccine Responses ◽  
Functional Homology ◽  
Vaccine Trials ◽  
Cd4 Binding Site ◽  
Human Igg1 ◽  
Hiv 1

Analyses of human clinical HIV-1 vaccine trials and preclinical vaccine studies performed in rhesus macaque (RM) models have identified associations between non-neutralizing Fc Receptor (FcR)-dependent antibody effector functions and reduced risk of infection. Specifically, antibody-dependent phagocytosis (ADP) has emerged as a common correlate of reduced infection risk in multiple RM studies and the human HVTN505 trial. This recurrent finding suggests that antibody responses with the capability to mediate ADP are most likely a desirable component of vaccine responses aimed at protecting against HIV-1 acquisition. As use of RM models is essential for development of the next generation of candidate HIV-1 vaccines, there is a need to determine how effectively ADP activity observed in RMs translates to activity in humans. In this study we compared ADP activity of human and RM monocytes and polymorphonuclear leukocytes (PMN) to bridge this gap in knowledge. We observed considerable variability in the magnitude of monocyte and PMN ADP activity across individual humans and RM that was not dependent on FcR alleles, and only modestly impacted by cell-surface levels of FcRs. Importantly, we found that for both human and RM phagocytes, ADP activity of antibodies targeting the CD4 binding site was greatest when mediated by human IgG3, followed by RM and human IgG1. These results demonstrate that there is functional homology between antibody and FcRs from these two species for ADP. We also used novel RM IgG1 monoclonal antibodies engineered with elongated hinge regions to show that hinge elongation augments RM ADP activity. The RM IgGs with engineered hinge regions can achieve ADP activity comparable to that observed with human IgG3. These novel modified antibodies will have utility in passive immunization studies aimed at defining the role of IgG3 and ADP in protection from virus challenge or control of disease in RM models. Our results contribute to a better translation of human and macaque antibody and FcR biology, and may help to improve testing accuracy and evaluations of future active and passive prevention strategies.

scholarly journals Recapitulation of HIV-1 Env-Antibody Coevolution in Macaques Leading to Neutralization Breadth

2020 ◽  
Author(s):  
Ryan S. Roark ◽  
Hui Li ◽  
Wilton B. Williams ◽  
Hema Chug ◽  
Rosemarie D. Mason ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Virus Antibody ◽  
Human Antibodies ◽  
Immunogen Design ◽  
Cd4 Binding Site ◽  
Human Immunodeficiency Viruses ◽  
Chemical Solutions ◽  
Developmental Features ◽  
Hiv 1

ABSTRACTNeutralizing antibodies elicited by HIV-1 coevolve with viral Envs in distinctive patterns, in some cases acquiring substantial breadth. Here we show that primary HIV-1 Envs, when expressed by simian-human immunodeficiency viruses in rhesus macaques, elicited patterns of Env-antibody coevolution strikingly similar to those in humans. This included conserved immunogenetic, structural and chemical solutions to epitope recognition and precise Env-amino acid substitutions, insertions and deletions leading to virus persistence. The structure of one rhesus antibody, capable of neutralizing 49% of a 208-strain panel, revealed a V2-apex mode of recognition like that of human bNAbs PGT145/PCT64-35M. Another rhesus antibody bound the CD4-binding site by CD4 mimicry mirroring human bNAbs 8ANC131/CH235/VRC01. Virus-antibody coevolution in macaques can thus recapitulate developmental features of human bNAbs, thereby guiding HIV-1 immunogen design.One sentence summaryVirus-antibody coevolution in rhesus macaques recapitulates developmental features of human antibodies.

scholarly journals Characterization of a vaccine-elicited human antibody with sequence homology to VRC01-class antibodies that binds the C1C2 gp120 domain

2021 ◽  
Author(s):  
Matthew D Gray ◽  
Junli Feng ◽  
Connor E Weidle ◽  
Kristen W Cohen ◽  
Lamar Ballweber-Fleming ◽  
...  
Keyword(s):  
B Cells ◽  
Binding Site ◽  
Sequence Homology ◽  
Human Antibody ◽  
Heavy Chains ◽  
Vaccine Trials ◽  
Class B ◽  
Cd4 Binding Site ◽  
Hiv 1

Broadly HIV-1 neutralizing VRC01-class antibodies bind the CD4-binding site of the HIV-1 envelope (Env) and contain VH1-2*02-derived heavy chains paired with light chains expressing five amino acid long CDRL3s. Their unmutated forms do not recognize Env or neutralize HIV-1. The lack of elicitation of VRC01-class antibodies in human clinical trials could potentially be due to the absence of activation of the corresponding naive B cells by the vaccine Env immunogens. To address this point directly, we examined Env-specific BCR sequences from participants in the HVTN 100 clinical trial. Of all the sequences analyzed only one displayed sequence homology to VRC01-class antibodies, but the corresponding antibody (FH1) recognized the C1C2 gp120 domain. For FH1 to switch epitope recognition to the CD4-binding site, alterations in both the CDRH3 and CDRL3 were necessary. Our findings support the use of specifically designed immunogens to activate VRC01-class B cells in future human vaccine trials.

scholarly journals Effects of gp120 Inner Domain (ID2) Immunogen Doses on Elicitation of Anti-HIV-1 Functional Fc-Effector Response to C1/C2 (Cluster A) Epitopes in Mice

2020 ◽  
Vol 8 (10) ◽  
pp. 1490
Author(s):  
Rebekah Sherburn ◽  
William D. Tolbert ◽  
Suneetha Gottumukkala ◽  
Guillaume Beaudoin-Bussières ◽  
Andrés Finzi ◽  
...  
Keyword(s):  
Passive Immunization ◽  
Neutralizing Antibody ◽  
Antibody Repertoire ◽  
Effector Functions ◽  
Dosing Strategies ◽  
Cluster A ◽  
Effector Response ◽  
Anti Hiv ◽  
Hiv 1

Fc-mediated effector functions of antibodies, including antibody-dependent cytotoxicity (ADCC), have been shown to contribute to vaccine-induced protection from HIV-1 infection, especially those directed against non-neutralizing, CD4 inducible (CD4i) epitopes within the gp120 constant 1 and 2 regions (C1/C2 or Cluster A epitopes). However, recent passive immunization studies have not been able to definitively confirm roles for these antibodies in HIV-1 prevention mostly due to the complications of cross-species Fc–FcR interactions and suboptimal dosing strategies. Here, we use our stabilized gp120 Inner domain (ID2) immunogen that displays the Cluster A epitopes within a minimal structural unit of HIV-1 Env to investigate an immunization protocol that induces a fine-tuned antibody repertoire capable of an effective Fc-effector response. This includes the generation of isotypes and the enhanced antibody specificity known to be vital for maximal Fc-effector activities, while minimizing the induction of isotypes know to be detrimental for these functions. Although our studies were done in in BALB/c mice we conclude that when optimally titrated for the species of interest, ID2 with GLA-SE adjuvant will elicit high titers of antibodies targeting the Cluster A region with potent Fc-mediated effector functions, making it a valuable immunogen candidate for testing an exclusive role of non-neutralizing antibody response in HIV-1 protection in vaccine settings.

scholarly journals Recapitulation of HIV-1 Env-antibody coevolution in macaques leading to neutralization breadth

Science ◽  
2020 ◽  
Vol 371 (6525) ◽  
pp. eabd2638
Author(s):  
Ryan S. Roark ◽  
Hui Li ◽  
Wilton B. Williams ◽  
Hema Chug ◽  
Rosemarie D. Mason ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Envelope Proteins ◽  
Viral Envelope ◽  
Immunogen Design ◽  
Cd4 Binding Site ◽  
Human Immunodeficiency Viruses ◽  
Chemical Solutions ◽  
Developmental Features ◽  
Hiv 1

Neutralizing antibodies elicited by HIV-1 coevolve with viral envelope proteins (Env) in distinctive patterns, in some cases acquiring substantial breadth. We report that primary HIV-1 envelope proteins—when expressed by simian-human immunodeficiency viruses in rhesus macaques—elicited patterns of Env-antibody coevolution very similar to those in humans, including conserved immunogenetic, structural, and chemical solutions to epitope recognition and precise Env–amino acid substitutions, insertions, and deletions leading to virus persistence. The structure of one rhesus antibody, capable of neutralizing 49% of a 208-strain panel, revealed a V2 apex mode of recognition like that of human broadly neutralizing antibodies (bNAbs) PGT145 and PCT64-35S. Another rhesus antibody bound the CD4 binding site by CD4 mimicry, mirroring human bNAbs 8ANC131, CH235, and VRC01. Virus-antibody coevolution in macaques can thus recapitulate developmental features of human bNAbs, thereby guiding HIV-1 immunogen design.

scholarly journals AAV-delivered eCD4-Ig protects rhesus macaques from high-dose SIVmac239 challenges

2019 ◽  
Vol 11 (502) ◽  
pp. eaau5409 ◽  
Author(s):  
Matthew R. Gardner ◽  
Christoph H. Fellinger ◽  
Lisa M. Kattenhorn ◽  
Meredith E. Davis-Gardner ◽  
Jesse A. Weber ◽  
...  
Keyword(s):  
Rhesus Macaques ◽  
Control Group ◽  
High Dose ◽  
Adeno Associated Virus ◽  
Viral Loads ◽  
Immune Pressure ◽  
Cd4 Binding Site ◽  
Human Immunodeficiency Viruses ◽  
Tier 3 ◽  
Hiv 1

A number of simian and simian human immunodeficiency viruses (SIV and SHIV, respectively) have been used to assess the efficacy of HIV-1 vaccine strategies. Among these, SIVmac239 is considered among the most stringent because, unlike SHIV models, its full genome has coevolved in its macaque host and its tier 3 envelope glycoprotein (Env) is exceptionally hard to neutralize. Here, we investigated the ability of eCD4-Ig, an antibody-like entry inhibitor that emulates the HIV-1 and SIV receptor and coreceptor, to prevent SIVmac239 infection. We show that rh-eCD4-IgI39N expressed by recombinant adeno-associated virus (AAV) vectors afforded four rhesus macaques complete protection from high-dose SIVmac239 challenges that infected all eight control macaques. However, rh-eCD4-IgI39N–expressing macaques eventually succumbed to serial escalating challenge doses that were 2, 8, 16, and 32 times the challenge doses that infected the control animals. Despite receiving greater challenge doses, these macaques had significantly lower peak and postpeak viral loads than the control group. Virus isolated from three of four macaques showed evidence of strong immune pressure from rh-eCD4-IgI39N, with mutations located in the CD4-binding site, which, in one case, exploited a point-mutation difference between rh-eCD4-IgI39N and rhesus CD4. Other escape pathways associated with clear fitness costs to the virus. Our data report effective protection of rhesus macaques from SIVmac239.

scholarly journals New SHIVs and Improved Design Strategy for Modeling HIV-1 Transmission, Immunopathogenesis, Prevention and Cure

2021 ◽  
Author(s):  
Hui Li ◽  
Shuyi Wang ◽  
Fang-Hua Lee ◽  
Ryan S. Roark ◽  
Alex I. Murphy ◽  
...  
Keyword(s):  
T Cells ◽  
Neutralizing Antibodies ◽  
Large Scale ◽  
Rhesus Macaques ◽  
Passive Immunization ◽  
Design Strategy ◽  
Efficient Replication ◽  
Hiv 1

Previously, we showed that substitution of HIV-1 Env residue 375-Ser by bulky aromatic residues enhances binding to rhesus CD4 and enables primary HIV-1 Envs to support efficient replication as simian-human immunodeficiency virus (SHIV) chimeras in rhesus macaques (RMs). Here, we test this design strategy more broadly by constructing SHIVs containing ten primary Envs corresponding to HIV-1 subtypes A, B, C, AE and AG. All ten SHIVs bearing wildtype Env375 residues replicated efficiently in human CD4+ T cells, but only one replicated efficiently in primary rhesus cells. This was a subtype AE SHIV that naturally contained His at Env375. Replacement of wildtype Env375 residues by Trp, Tyr, Phe or His in the other nine SHIVs led to efficient replication in rhesus CD4+ T cells in vitro and in vivo. Nine SHIVs containing optimized Env375 alleles were grown large-scale in primary rhesus CD4+ T cells to serve as challenge stocks in preclinical prevention trials. These virus stocks were genetically homogeneous, native-like in Env antigenicity and tier-2 neutralization sensitivity, and transmissible by rectal, vaginal, penile, oral or intravenous routes. To facilitate future SHIV constructions, we engineered a simplified second-generation design scheme and validated it in RMs. Overall, our findings demonstrate that SHIVs bearing primary Envs with bulky aromatic substitutions at Env375 consistently replicate in RMs, recapitulating many features of HIV-1 infection in humans. Such SHIVs are efficiently transmitted by mucosal routes common to HIV-1 infection and can be used to test vaccine efficacy in preclinical monkey trials. Importance SHIV infection of Indian rhesus macaques is an important animal model for studying HIV-1 transmission, prevention, immunopathogenesis and cure. Such research is timely, given recent progress with active and passive immunization and novel approaches to HIV-1 cure. Given the multifaceted roles of HIV-1 Env in cell tropism and virus entry, and as a target for neutralizing and non-neutralizing antibodies, Envs selected for SHIV construction are of paramount importance. Until recently, it has been impossible to strategically design SHIVs bearing clinically relevant Envs that replicate consistently in monkeys. This changed with the discovery that bulky aromatic substitutions at residue Env375 confer enhanced affinity to rhesus CD4. Here, we show that 10 new SHIVs bearing primary HIV-1 Envs with residue 375 substitutions replicated efficiently in RMs and could be transmitted efficiently across rectal, vaginal, penile and oral mucosa. These findings suggest an expanded role for SHIVs as a model of HIV-1 infection.

scholarly journals Sensitivity to Broadly Neutralizing Antibodies of Recently Transmitted HIV-1 Clade CRF02_AG Viruses with a Focus on Evolution over Time

2018 ◽  
Vol 93 (2) ◽  
Author(s):  
Karl Stefic ◽  
Mélanie Bouvin-Pley ◽  
Asma Essat ◽  
Clara Visdeloup ◽  
Alain Moreau ◽  
...  
Keyword(s):  
Clinical Trials ◽  
West Africa ◽  
Neutralizing Antibodies ◽  
Passive Immunization ◽  
Broadly Neutralizing Antibodies ◽  
Human Monoclonal Antibodies ◽  
Large Panel ◽  
Cd4 Binding Site ◽  
Major Progress ◽  
Hiv 1

ABSTRACT Broadly neutralizing antibodies (bnAbs) are promising agents for prevention and/or treatment of HIV-1 infection. However, the diversity among HIV-1 envelope (Env) glycoproteins impacts bnAb potency and breadth. Neutralization data on the CRF02_AG clade are scarce although it is highly prevalent in West Africa and Europe. We assessed the sensitivity to bnAbs of a panel of 33 early transmitted CRF02_AG viruses over a 15-year period of the French epidemic (1997 to 2012). Env pseudotyped CRF02_AG viruses were best neutralized by the CD4 binding site (CD4bs)-directed bnAbs (VRC01, 3BNC117, NIH45-46G54W, and N6) and the gp41 membrane-proximal external region (MPER)-directed bnAb 10E8 in terms of both potency and breadth. We observed a higher resistance to bnAbs targeting the V1V2-glycan region (PG9 and PGT145) and the V3-glycan region (PGT121 and 10-1074). Combinations were required to achieve full coverage across this subtype. We observed increased resistance to bnAbs targeting the CD4bs linked to the diversification of CRF02_AG Env over the course of the epidemic, a phenomenon which was previously described for subtypes B and C. These data on the sensitivity to bnAbs of CRF02_AG viruses, including only recently transmitted viruses, will inform future passive immunization studies. Considering the drift of the HIV-1 species toward higher resistance to neutralizing antibodies, it appears necessary to keep updating existing panels for evaluation of future vaccine and passive immunization studies. IMPORTANCE Major progress occurred during the last decade leading to the isolation of human monoclonal antibodies, termed broadly neutralizing antibodies (bnAbs) due to their capacity to neutralize various strains of HIV-1. Several clinical trials are under way in order to evaluate their efficacy in preventive or therapeutic strategies. However, no single bnAb is active against 100% of strains. It is important to gather data on the sensitivity to neutralizing antibodies of all genotypes, especially those more widespread in regions where the prevalence of HIV-1 infection is high. Here, we assembled a large panel of clade CRF02_AG viruses, the most frequent genotype circulating in West Africa and the second most frequent found in several European countries. We evaluated their sensitivities to bnAbs, including those most advanced in clinical trials, and looked for the best combinations. In addition, we observed a trend toward increased resistance to bnAbs over the course of the epidemic.

The role of conventional antibodies targeting the CD4 binding site and CD4-induced epitopes in the control of HIV-1 CRF01_AE viruses

2019 ◽  
Vol 508 (1) ◽  
pp. 46-51 ◽  
Author(s):  
Win Thida ◽  
Takeo Kuwata ◽  
Yosuke Maeda ◽  
Tetsu Yamashiro ◽  
Giang Van Tran ◽  
...  
Keyword(s):  
Binding Site ◽  
Cd4 Binding Site ◽  
Hiv 1

scholarly journals A Human IgG1 (b12) Specific for the CD4 Binding Site of HIV-1 Neutralizes by Inhibiting the Virus Fusion Entry Process, but b12 Fab Neutralizes by Inhibiting a Postfusion Event

Virology ◽  
1997 ◽  
Vol 233 (2) ◽  
pp. 313-326 ◽  
Author(s):  
Tracey L. McInerney ◽  
Lesley McLain ◽  
Sylvia J. Armstrong ◽  
Nigel J. Dimmock
Keyword(s):  
Binding Site ◽  
Virus Fusion ◽  
Cd4 Binding Site ◽  
Human Igg1 ◽  
Hiv 1

scholarly journals Efficacy of Multivalent Adenovirus-Based Vaccine against Simian Immunodeficiency Virus Challenge

2009 ◽  
Vol 84 (6) ◽  
pp. 2996-3003 ◽  
Author(s):  
Danilo R. Casimiro ◽  
Kara Cox ◽  
Aimin Tang ◽  
Kara J. Sykes ◽  
Meizhen Feng ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Rhesus Macaques ◽  
High Dose ◽  
Virus Challenge ◽  
Study Results ◽  
Immunodeficiency Virus ◽  
Virological Outcomes ◽  
Serotype 5 ◽  
Hiv 1 ◽  
Simian Immunodeficiency Virus Challenge

ABSTRACT The prophylactic efficacies of several multivalent replication-incompetent adenovirus serotype 5 (Ad5) vaccines were examined in rhesus macaques using an intrarectal high-dose simian immunodeficiency virus SIVmac239 challenge model. Cohorts of Mamu-A*01+/B*17− Indian rhesus macaques were immunized with one of several combinations of Ad5 vectors expressing Gag, Pol, Nef, and Env gp140; for comparison, a Mamu-A*01+ cohort was immunized using the Ad5 vector alone. There was no sign of immunological interference between antigens in the immunized animals. In general, expansion of the antigen breadth resulted in more favorable virological outcomes. In particular, the order of efficacy trended as follows: Gag/Pol/Nef/Env ≈ Gag/Pol > Gag ≈ Gag/Pol/Nef > Nef. However, the precision in ranking the vaccines based on the study results may be limited by the cohort size, and as such, may warrant additional testing. The implications of these results in light of the recent discouraging results of the phase IIb study of the trivalent Ad5 HIV-1 vaccine are discussed.

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