Tissue memory B cell repertoire analysis after ALVAC/AIDSVAX B/E gp120 immunization of rhesus macaques

Luo, Kan; Liao, Hua‐Xin; Zhang, Ruijun; Easterhoff, David; Wiehe, Kevin; Gurley, Thaddeus C.; Armand, Lawrence; Allen, Ashley A.; Holle, Tarra A. Von; Marshall, Dawn J.; Whitesides, John F.; Pritchett, Jamie; Foulger, Andrew; Hernandéz, Giovanna; Parks, Robert; Lloyd, Krissey E.; Stolarchuk, Christina; Peel, Jessica N.; Yates, Nicole L.; Dunford, Erika; Arora, Sabrina; Wang, Amy; Bowman, Cindy; Sutherland, Laura L.; Scearce, Richard M.; Xia, Shi-Mao; Bonsignori, Mattia; Pollara, Justin; Edwards, R. Whitney; Santra, Sampa; Letvin, Norman L.; Tartaglia, James; Francis, Donald P.; Sinangil, Faruk; Lee, Carter; Kaewkungwal, Jaranit; Nitayaphan, Sorachai; Pitisuttithum, Punnee; Rerks-Ngarm, Supachai; Michael, Nelson L.; Kim, Jerome H.; Alam, S. Munir; Vandergrift, Nathan; Ferrari, Guido; Montefiori, David C.; Tomaras, Georgia D.; Haynes, Barton F.; Moody, M. Anthony

doi:10.1172/jci.insight.88522

Cited by 12 publications

(19 citation statements)

References 44 publications

(63 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, we detected only memory B cells in blood and only plasma cells in the BM, which we interpret to represent the GC output. We did not detect Env-specific B cells in the ileum despite high numbers of total IgG memory B cells and plasma cells in this compartment, in agreement with a previous vaccination study (Luo et al, 2016) and a study of total B cell repertoires in humans, demonstrating limited exchange between the gut and peripheral blood B cell repertoires (Meng et al, 2017). This finding, however, does not rule out that soluble IgG induced by i.m.…”

Section: Discussionsupporting

confidence: 92%

Extensive dissemination and intraclonal maturation of HIV Env vaccine-induced B cell responses

Phad

Pushparaj

Tran

et al. 2019

Journal of Experimental Medicine

View full text Add to dashboard Cite

Well-ordered HIV-1 envelope glycoprotein (Env) trimers are prioritized for clinical evaluation, and there is a need for an improved understanding about how elicited B cell responses evolve following immunization. To accomplish this, we prime-boosted rhesus macaques with clade C NFL trimers and identified 180 unique Ab lineages from ∼1,000 single-sorted Env-specific memory B cells. We traced all lineages in high-throughput heavy chain (HC) repertoire (Rep-seq) data generated from multiple immune compartments and time points and expressed several as monoclonal Abs (mAbs). Our results revealed broad dissemination and high levels of somatic hypermutation (SHM) of most lineages, including tier 2 virus neutralizing lineages, following boosting. SHM was highest in the Ab complementarity determining regions (CDRs) but also surprisingly high in the framework regions (FRs), especially FR3. Our results demonstrate the capacity of the immune system to affinity-mature large numbers of Env-specific B cell lineages simultaneously, supporting the use of regimens consisting of repeated boosts to improve each Ab, even those belonging to less expanded lineages.

show abstract

Section: Discussionsupporting

confidence: 92%

Extensive dissemination and intraclonal maturation of HIV Env vaccine-induced B cell responses

Phad

Pushparaj

Tran

et al. 2019

Journal of Experimental Medicine

View full text Add to dashboard Cite

show abstract

“…Moreover, our study was also limited in that we were unable to compare humoral responses in our animal models to those observed in human clinical trials. While preclinical HIV-1 vaccine studies performed in RM and human clinical trials have been shown to recapitulate safety and immunogenicity results (45, 87–92), the rabbit model has not been compared in similar detail. However, translation of studies performed in the rabbit model to studies performed in RM and humans aided in the development of next-generation anthrax vaccine regimens (93–96).…”

Section: Discussionmentioning

confidence: 99%

Bridging Vaccine-Induced HIV-1 Neutralizing and Effector Antibody Responses in Rabbit and Rhesus Macaque Animal Models

Pollara

Jones

Huffman

et al. 2019

J Virol

Self Cite

View full text Add to dashboard Cite

Studies in animal models are essential prerequisites for clinical trials of candidate HIV vaccines. Small animals, such as rabbits, are used to evaluate promising strategies prior to further immunogenicity and efficacy testing in nonhuman primates. Our goal was to determine how HIV-specific vaccine-elicited antibody responses, epitope specificity, and Fc-mediated functions in the rabbit model can predict those in the rhesus macaque (RM) model. Detailed comparisons of the HIV-1-specific IgG response were performed on serum from rabbits and RM given identical modified vaccinia virus Ankara-prime/gp120-boost immunization regimens. We found that vaccine-induced neutralizing antibody, gp120-binding antibody levels and immunodominant specificities, antibody-dependent cellular phagocytosis of HIV-1 virions, and antibody-dependent cellular cytotoxicity (ADCC) responses against gp120-coated target cells were similar in rabbits and RM. However, we also identified characteristics of humoral immunity that differed across species. ADCC against HIV-infected target cells was elicited in rabbits but not in RM, and we observed differences among subdominantly targeted epitopes. Human Fc receptor binding assays and analysis of antibody-cell interactions indicated that rabbit vaccine-induced antibodies effectively recruited and activated human natural killer cells, while vaccine-elicited RM antibodies were unable to activate either human or RM NK cells. Thus, our data demonstrate that both Fc-independent and Fc-dependent functions of rabbit antibodies can be measured with commonly usedin vitroassays; however, the ability of immunogenicity studies performed in rabbits to predict responses in RM will vary depending on the particular immune parameter of interest.IMPORTANCENonneutralizing antibody functions have been associated with reduced infection risk, or control of virus replication, for HIV-1 and related viruses. It is therefore critical to evaluate development of these responses throughout all stages of preclinical testing. Rabbits are conventionally used to evaluate the ability of vaccine candidates to safely elicit antibodies that bind and neutralize HIV-1. However, it remained unexplored how effectively rabbits model the development of nonneutralizing antibody responses in primates. We administered identical HIV-1 vaccine regimens to rabbits and rhesus macaques and performed detailed comparisons of vaccine-induced antibody responses. We demonstrated that nonneutralizing HIV-specific antibody responses can be studied in the rabbit model and have identified aspects of these responses that are common, and those that are unique, to rabbits and rhesus macaques. Our findings will help determine how to best utilize preclinical rabbit and rhesus macaque models to accelerate HIV vaccine candidate testing in human trials.

show abstract

“…We have previously described a high‐throughput quantitative flow cytometry‐based assay that allows for detection of the proteolytic activity of Granzyme B (GzB) at the single cell level to identify target cells that have received a cytotoxic hit as a result of antigen‐specific antibody‐Fc receptor interactions . We and others have broadly applied this assay, the ADCC‐GranToxiLux assay (ADCC‐GTL), to the measure of HIV‐ or SIV‐specific antibody responses generated by natural infection or by active and passive immunization strategies .…”

mentioning

confidence: 99%

Application of area scaling analysis to identify natural killer cell and monocyte involvement in the GranToxiLux antibody dependent cell‐mediated cytotoxicity assay

et al. 2018

Self Cite

View full text Add to dashboard Cite

Several different assay methodologies have been described for the evaluation of HIV or SIV‐specific antibody‐dependent cell‐mediated cytotoxicity (ADCC). Commonly used assays measure ADCC by evaluating effector cell functions, or by detecting elimination of target cells. Signaling through Fc receptors, cellular activation, cytotoxic granule exocytosis, or accumulation of cytolytic and immune signaling factors have been used to evaluate ADCC at the level of the effector cells. Alternatively, assays that measure killing or loss of target cells provide a direct assessment of the specific killing activity of antibodies capable of ADCC. Thus, each of these two distinct types of assays provides information on only one of the critical components of an ADCC event; either the effector cells involved, or the resulting effect on the target cell. We have developed a simple modification of our previously described high‐throughput ADCC GranToxiLux (GTL) assay that uses area scaling analysis (ASA) to facilitate simultaneous quantification of ADCC activity at the target cell level, and assessment of the contribution of natural killer cells and monocytes to the total observed ADCC activity when whole human peripheral blood mononuclear cells are used as a source of effector cells. The modified analysis method requires no additional reagents and can, therefore, be easily included in prospective studies. Moreover, ASA can also often be applied to pre‐existing ADCC‐GTL datasets. Thus, incorporation of ASA to the ADCC‐GTL assay provides an ancillary assessment of the ability of natural and vaccine‐induced antibodies to recruit natural killer cells as well as monocytes against HIV or SIV; or to any other field of research for which this assay is applied. © 2018 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of ISAC.

show abstract

Tissue memory B cell repertoire analysis after ALVAC/AIDSVAX B/E gp120 immunization of rhesus macaques

Cited by 12 publications

References 44 publications

Extensive dissemination and intraclonal maturation of HIV Env vaccine-induced B cell responses

Extensive dissemination and intraclonal maturation of HIV Env vaccine-induced B cell responses

Bridging Vaccine-Induced HIV-1 Neutralizing and Effector Antibody Responses in Rabbit and Rhesus Macaque Animal Models

Application of area scaling analysis to identify natural killer cell and monocyte involvement in the GranToxiLux antibody dependent cell‐mediated cytotoxicity assay

Contact Info

Product

Resources

About