Differential V2-directed Antibody Responses in Non-human Primates Infected with SHIVs or Immunized with Diverse HIV Vaccines

Abstract V2p and V2i antibodies (Abs) that are specific for epitopes in the V1V2 region of the HIV gp120 envelope (Env) do not effectively neutralize HIV but mediate Fc-dependent anti-viral activities that have been correlated with protection from, or control of HIV, SIV and SHIV infection. Here, we describe a novel molecular toolbox that allows the discrimination of antigenically and functionally distinct polyclonal V2 Ab responses. We identified different patterns of V2 Ab induction by SHIV infection and three separate vaccine regimens that will aid in fine tuning an optimized immunization protocol for inducing V2p and V2i Abs. We observed no, or weak and sporadic V2p and V2i Abs in non-vaccinated Tier 1 and Tier 2 SHIV-infected NHPs, but in contrast, strong V2p and/or V2i Ab responses after immunization with a V2-targeting vaccine protocol using a prime/boost regimen with gp120 DNA and a V1V2-scaffold protein. The V2-targeting vaccine protocol is superior to both natural infection and to immunization with whole Env constructs for inducing functional V2p- and V2i-specific responses. Strikingly, levels of V2-directed Abs correlated inversely with Abs specific for gp120 and peptides of V3 and C5. These data demonstrate that a V1V2-targeting vaccine have advantages over the imprecise targeting of SIV/SHIV infections and of whole Env-based immunization regimens for inducing a more focused functional V2p- and V2i-specific Ab response.

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Antibody responses induced by SHIV infection are more focused than those induced by soluble native HIV-1 envelope trimers in non-human primates

PLoS Pathogens ◽

10.1371/journal.ppat.1009736 ◽

2021 ◽

Vol 17 (8) ◽

pp. e1009736

Author(s):

Jelle van Schooten ◽

Marlies M. van Haaren ◽

Hui Li ◽

Laura E. McCoy ◽

Colin Havenar-Daughton ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Natural Infection ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Broadly Neutralizing Antibodies ◽

Antibody Diversity ◽

Infected Infant ◽

Immunodeficiency Virus ◽

Shiv Infection ◽

Hiv 1

The development of an effective human immunodeficiency virus (HIV-1) vaccine is a high global health priority. Soluble native-like HIV-1 envelope glycoprotein trimers (Env), including those based on the SOSIP design, have shown promise as vaccine candidates by inducing neutralizing antibody responses against the autologous virus in animal models. However, to overcome HIV-1’s extreme diversity a vaccine needs to induce broadly neutralizing antibodies (bNAbs). Such bNAbs can protect non-human primates (NHPs) and humans from infection. The prototypic BG505 SOSIP.664 immunogen is based on the BG505 env sequence isolated from an HIV-1-infected infant from Kenya who developed a bNAb response. Studying bNAb development during natural HIV-1 infection can inform vaccine design, however, it is unclear to what extent vaccine-induced antibody responses to Env are comparable to those induced by natural infection. Here, we compared Env antibody responses in BG505 SOSIP-immunized NHPs with those in BG505 SHIV-infected NHPs, by analyzing monoclonal antibodies (mAbs). We observed three major differences between BG505 SOSIP immunization and BG505 SHIV infection. First, SHIV infection resulted in more clonal expansion and less antibody diversity compared to SOSIP immunization, likely because of higher and/or prolonged antigenic stimulation and increased antigen diversity during infection. Second, while we retrieved comparatively fewer neutralizing mAbs (NAbs) from SOSIP-immunized animals, these NAbs targeted more diverse epitopes compared to NAbs from SHIV-infected animals. However, none of the NAbs, either elicited by vaccination or infection, showed any breadth. Finally, SOSIP immunization elicited antibodies against the base of the trimer, while infection did not, consistent with the base being placed onto the virus membrane in the latter setting. Together these data provide new insights into the antibody response against BG505 Env during infection and immunization and limitations that need to be overcome to induce better responses after vaccination.

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Neutralizing Antibody Responses following Long-Term Vaccination with HIV-1 Env gp140 in Guinea Pigs

Journal of Virology ◽

10.1128/jvi.00369-18 ◽

2018 ◽

Vol 92 (13) ◽

pp. e00369-18 ◽

Cited By ~ 7

Author(s):

Christine A. Bricault ◽

James M. Kovacs ◽

Alexander Badamchi-Zadeh ◽

Krisha McKee ◽

Jennifer L. Shields ◽

...

Keyword(s):

Guinea Pigs ◽

Neutralizing Antibodies ◽

Antibody Responses ◽

Tier 2 ◽

Broadly Neutralizing Antibodies ◽

Vaccination Regimen ◽

Tier 1 ◽

Clade C ◽

Hiv 1

ABSTRACTA vaccination regimen capable of eliciting potent and broadly neutralizing antibodies (bNAbs) remains an unachieved goal of the HIV-1 vaccine field. Here, we report the immunogenicity of longitudinal prime/boost vaccination regimens with a panel of HIV-1 envelope (Env) gp140 protein immunogens over a period of 200 weeks in guinea pigs. We assessed vaccine regimens that included a monovalent clade C gp140 (C97ZA012 [C97]), a tetravalent regimen consisting of four clade C gp140s (C97ZA012, 459C, 405C, and 939C [4C]), and a tetravalent regimen consisting of clade A, B, C, and mosaic gp140s (92UG037, PVO.4, C97ZA012, and Mosaic 3.1, respectively [ABCM]). We found that the 4C and ABCM prime/boost regimens were capable of eliciting greater magnitude and breadth of binding antibody responses targeting variable loop 2 (V2) over time than the monovalent C97-only regimen. The longitudinal boosting regimen conducted over more than 2 years increased the magnitude of certain tier 1 NAb responses but did not increase the magnitude or breadth of heterologous tier 2 NAb responses. These data suggest that additional immunogen design strategies are needed to induce broad, high-titer tier 2 NAb responses.IMPORTANCEThe elicitation of potent, broadly neutralizing antibodies (bNAbs) remains an elusive goal for the HIV-1 vaccine field. In this study, we explored the use of a long-term vaccination regimen with different immunogens to determine if we could elicit bNAbs in guinea pigs. We found that longitudinal boosting over more than 2 years increased tier 1 NAb responses but did not increase the magnitude and breadth of tier 2 NAb responses. These data suggest that additional immunogen designs and vaccination strategies will be necessary to induce broad tier 2 NAb responses.

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Immunogenicity of NYVAC Prime-Protein Boost Human Immunodeficiency Virus Type 1 Envelope Vaccination and Simian-Human Immunodeficiency Virus Challenge of Nonhuman Primates

Journal of Virology ◽

10.1128/jvi.02035-17 ◽

2018 ◽

Vol 92 (8) ◽

pp. e02035-17 ◽

Cited By ~ 4

Author(s):

Kevin O. Saunders ◽

Sampa Santra ◽

Robert Parks ◽

Nicole L. Yates ◽

Laura L. Sutherland ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Vaccine Trial ◽

Antibody Responses ◽

Tier 2 ◽

Immunodeficiency Virus ◽

Shiv Infection ◽

Hiv 1

ABSTRACTA preventive human immunodeficiency virus type 1 (HIV-1) vaccine is an essential part of the strategy to eradicate AIDS. A critical question is whether antibodies that do not neutralize primary isolate (tier 2) HIV-1 strains can protect from infection. In this study, we investigated the ability of an attenuated poxvirus vector (NYVAC) prime-envelope gp120 boost to elicit potentially protective antibody responses in a rhesus macaque model of mucosal simian-human immunodeficiency virus (SHIV) infection. NYVAC vector delivery of a group M consensus envelope, trivalent mosaic envelopes, or a natural clade B isolate B.1059 envelope elicited antibodies that mediated neutralization of tier 1 viruses, cellular cytotoxicity, and phagocytosis. None of the macaques made neutralizing antibodies against the tier 2 SHIV SF162P3 used for mucosal challenge. Significant protection from infection was not observed for the three groups of vaccinated macaques compared to unvaccinated macaques, although binding antibody to HIV-1 Env correlated with decreased viremia after challenge. Thus, NYVAC Env prime-gp120 boost vaccination elicited polyfunctional, nonneutralizing antibody responses with minimal protective activity against tier 2 SHIV mucosal challenge.IMPORTANCEThe antibody responses that confer protection against HIV-1 infection remain unknown. Polyfunctional antibody responses correlated with time to infection in previous macaque studies. Determining the ability of vaccines to induce these types of responses is critical for understanding how to improve upon the one efficacious human HIV-1 vaccine trial completed thus far. We characterized the antibody responses induced by a NYVAC-protein vaccine and determined the protective capacity of polyfunctional antibody responses in an R5, tier 2 mucosal SHIV infection model.

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Optimal Timing for Launching Installation of Tier 2 and 3 Systems of School-Wide Positive Behavioral Interventions and Supports

Journal of Positive Behavior Interventions ◽

10.1177/1098300721996084 ◽

2021 ◽

pp. 109830072199608

Author(s):

Angus Kittelman ◽

Sterett H. Mercer ◽

Kent McIntosh ◽

Robert Hoselton

Keyword(s):

Longitudinal Study ◽

Behavioral Interventions ◽

Structural Equation ◽

Equation Modeling ◽

Optimal Timing ◽

First Year ◽

Tier 2 ◽

Positive Behavioral Interventions ◽

Tier 1 ◽

Tier 3

The purpose of this longitudinal study was to examine patterns in implementation of Tier 2 and 3 school-wide positive behavioral interventions and supports (SWPBIS) systems to identify timings of installation that led to higher implementation of advanced tiers. Extant data from 776 schools in 27 states reporting on the first 3 years of Tier 2 implementation and 359 schools in 23 states reporting on the first year of Tier 3 implementation were analyzed. Using structural equation modeling, we found that higher Tier 1 implementation predicted subsequent Tier 2 and Tier 3 implementation. In addition, waiting 2 or 3 years after initial Tier 1 implementation to launch Tier 2 systems predicted higher initial Tier 2 implementation (compared with implementing the next year). Finally, we found that launching Tier 3 systems after Tier 2 systems, compared with launching both tiers simultaneously, predicted higher Tier 2 implementation in the second and third year, so long as Tier 3 systems were launched within 3 years of Tier 2 systems. These findings provide empirical guidance for when to launch Tier 2 and 3 systems; however, we emphasize that delays in launching advanced systems should not equate to delays in more intensive supports for students.

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Global Inland Capture and Culture Finfisheries Follow Different Trends When Evaluated by the Human Development Index

Sustainability ◽

10.3390/su13158420 ◽

2021 ◽

Vol 13 (15) ◽

pp. 8420

Author(s):

Peter W. Sorensen ◽

Maria Lourdes D. Palomares

Keyword(s):

Socioeconomic Factors ◽

Human Development ◽

Human Development Index ◽

Developed Countries ◽

Global Scale ◽

Tier 2 ◽

Development Index ◽

Tier 1 ◽

Catch Reconstruction ◽

Tier 3

To assess whether and how socioeconomic factors might be influencing global freshwater finfisheries, inland fishery data reported to the FAO between 1950 and 2015 were grouped by capture and culture, country human development index, plotted, and compared. We found that while capture inland finfishes have greatly increased on a global scale, this trend is being driven almost entirely by poorly developed (Tier-3) countries which also identify only 17% of their catch. In contrast, capture finfisheries have recently plateaued in moderately-developed (Tier-2) countries which are also identifying 16% of their catch but are dominated by a single country, China. In contrast, reported capture finfisheries are declining in well-developed (Tier-1) countries which identify nearly all (78%) of their fishes. Simultaneously, aquacultural activity has been increasing rapidly in both Tier-2 and Tier-3 countries, but only slowly in Tier-1 countries; remarkably, nearly all cultured species are being identified by all tier groups. These distinctly different trends suggest that socioeconomic factors influence how countries report and conduct capture finfisheries. Reported rapid increases in capture fisheries are worrisome in poorly developed countries because they cannot be explained and thus these fisheries cannot be managed meaningfully even though they depend on them for food. Our descriptive, proof-of-concept study suggests that socioeconomic factors should be considered in future, more sophisticated efforts to understand global freshwater fisheries which might include catch reconstruction.

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Seismic characteristics of polygonal fault systems in the Great South Basin, New Zealand

Open Geosciences ◽

10.1515/geo-2020-0177 ◽

2020 ◽

Vol 12 (1) ◽

pp. 851-865

Author(s):

Sukonmeth Jitmahantakul ◽

Piyaphong Chenrai ◽

Pitsanupong Kanjanapayont ◽

Waruntorn Kanitpanyacharoen

Keyword(s):

Three Dimensional ◽

Late Eocene ◽

Seismic Survey ◽

Fault System ◽

Normal Faults ◽

Tier 2 ◽

South Basin ◽

Fault Systems ◽

Tier 1 ◽

Polygonal Fault

AbstractA well-developed multi-tier polygonal fault system is located in the Great South Basin offshore New Zealand’s South Island. The system has been characterised using a high-quality three-dimensional seismic survey tied to available exploration boreholes using regional two-dimensional seismic data. In this study area, two polygonal fault intervals are identified and analysed, Tier 1 and Tier 2. Tier 1 coincides with the Tucker Cove Formation (Late Eocene) with small polygonal faults. Tier 2 is restricted to the Paleocene-to-Late Eocene interval with a great number of large faults. In map view, polygonal fault cells are outlined by a series of conjugate pairs of normal faults. The polygonal faults are demonstrated to be controlled by depositional facies, specifically offshore bathyal deposits characterised by fine-grained clays, marls and muds. Fault throw analysis is used to understand the propagation history of the polygonal faults in this area. Tier 1 and Tier 2 initiate at about Late Eocene and Early Eocene, respectively, based on their maximum fault throws. A set of three-dimensional fault throw images within Tier 2 shows that maximum fault throws of the inner polygonal fault cell occurs at the same age, while the outer polygonal fault cell exhibits maximum fault throws at shallower levels of different ages. The polygonal fault systems are believed to be related to the dewatering of sedimentary formation during the diagenesis process. Interpretation of the polygonal fault in this area is useful in assessing the migration pathway and seal ability of the Eocene mudstone sequence in the Great South Basin.

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Incorporation of plasma-based next-generation sequencing to improve guideline-concordant molecular testing in patients with newly diagnosed metastatic nonsquamous non-small cell lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.39.28_suppl.14 ◽

2021 ◽

Vol 39 (28_suppl) ◽

pp. 14-14

Author(s):

Charu Aggarwal ◽

Melina Elpi Marmarelis ◽

Wei-Ting Hwang ◽

Dylan G. Scholes ◽

Aditi Puri Singh ◽

...

Keyword(s):

Clinical Practice ◽

Practice Change ◽

Molecular Testing ◽

Tier 2 ◽

Newly Diagnosed ◽

Next Generation ◽

First Line ◽

Tier 1 ◽

Tier 3 ◽

The Impact

14 Background: Current NCCN guidelines recommend comprehensive molecular profiling for all newly diagnosed patients with metastatic non-squamous NSCLC to enable the delivery of personalized medicine. We have previously demonstrated that incorporation of plasma based next-generation gene sequencing (NGS) improves detection of clinically actionable mutations in patients with advanced NSCLC (Aggarwal et al, JAMA Oncology, 2018). To increase rates of comprehensive molecular testing at our institution, we adapted our clinical practice to include concurrent use of plasma (P) and tissue (T) based NGS upon initial diagnosis. P NGS testing was performed using a commercial 74 gene assay. We analyzed the impact of this practice change on guideline concordant molecular testing at our institution. Methods: A retrospective cohort study of patients with newly diagnosed metastatic non-squamous NSCLC following the implementation of this practice change in 12/2018 was performed. Tiers of NCCN guideline concordant testing were defined, Tier 1: complete EGFR, ALK, BRAF, ROS1, MET, RET, NTRK testing, Tier 2: included above, but with incomplete NTRK testing, Tier 3: > 2 genes tested, Tier 4: single gene testing, Tier 5: no testing. Proportion of patients with comprehensive molecular testing by modality (T NGS vs. T+P NGS) were compared using one-sided Fisher’s exact test. Results: Between 01/2019, and 12/2019, 170 patients with newly diagnosed metastatic non-Sq NSCLC were treated at our institution. Overall, 98.2% (167/170) patients underwent molecular testing, Tier 1: n = 100 (59%), Tier 2: n = 39 (23%), Tier 3/4: n = 28 (16.5%), Tier 5: n = 3 (2%). Amongst these patients, 43.1% (72/167) were tested with T NGS alone, 8% (15/167) with P NGS alone, and 47.9% (80/167) with T+P NGS. A higher proportion of patients underwent comprehensive molecular testing (Tiers 1+2) using T+P NGS: 95.7% (79/80) compared to T alone: 62.5% (45/72), p < 0.0005. Prior to the initiation of first line treatment, 72.4% (123/170) patients underwent molecular testing, Tier 1: n = 73 (59%), Tier 2: n = 27 (22%) and Tier 3/4: n = 23 (18%). Amongst these, 39% (48/123) were tested with T NGS alone, 7% (9/123) with P NGS alone and 53.6% (66/123) with T+P NGS. A higher proportion of patients underwent comprehensive molecular testing (Tiers 1+2) using T+P NGS, 100% (66/66) compared to 52% (25/48) with T NGS alone (p < 0.0005). Conclusions: Incorporation of concurrent T+P NGS testing in treatment naïve metastatic non-Sq NSCLC significantly increased the proportion of patients undergoing guideline concordant molecular testing, including prior to initiation of first-line therapy at our institution. Concurrent T+P NGS should be adopted into institutional pathways and routine clinical practice.

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Abstract P192: Metabolomic Profiles Associated with Coronary Heart Disease in Women

Circulation ◽

10.1161/circ.133.suppl_1.p192 ◽

2016 ◽

Vol 133 (suppl_1) ◽

Author(s):

Nina P Paynter ◽

Raji Balasubramanian ◽

Shuba Gopal ◽

Franco Giulianini ◽

Leslie Tinker ◽

...

Keyword(s):

Risk Factors ◽

Coronary Heart Disease ◽

Logistic Regression ◽

Heart Disease ◽

Tier 2 ◽

Validation Data ◽

Data Set ◽

Chd Risk ◽

Tier 1 ◽

Chd Risk Factors

Background: Prior studies of metabolomic profiles and coronary heart disease (CHD) have been limited by relatively small case numbers and scant data in women. Methods: The discovery set examined 371 metabolites in 400 confirmed, incident CHD cases and 400 controls (frequency matched on age, race/ethnicity, hysterectomy status and time of enrollment) in the Women’s Health Initiative Observational Study (WHI-OS). All selected metabolites were validated in a separate set of 394 cases and 397 matched controls drawn from the placebo arms of the WHI Hormone Therapy trials and the WHI-OS. Discovery used 4 methods: false-discovery rate (FDR) adjusted logistic regression for individual metabolites, permutation corrected least absolute shrinkage and selection operator (LASSO) algorithms, sparse partial least squares discriminant analysis (PLS-DA) algorithms, and random forest algorithms. Each method was performed with matching factors only and with matching plus both medication use (aspirin, statins, anti-diabetics and anti-hypertensives) and traditional CHD risk factors (smoking, systolic blood pressure, diabetes, total and HDL cholesterol). Replication in the validation set was defined as a logistic regression coefficient of p<0.05 for the metabolites selected by 3 or 4 methods (tier 1), or a FDR adjusted p<0.05 for metabolites selected by only 1 or 2 methods (tier 2). Results: Sixty-seven metabolites were selected in the discovery data set (30 tier 1 and 37 tier 2). Twenty-six successfully replicated in the validation data set (21 tier 1 and 5 tier 2), with 25 significant with adjusting for matching factors only and 11 significant after additionally adjusting for medications and CHD risk factors. Validated metabolites included amino acids, sugars, nucleosides, eicosanoids, plasmologens, polyunsaturated phospholipids and highly saturated triglycerides. These include novel metabolites as well as metabolites such as glutamate/glutamine, which have been shown in other populations. Conclusions: Multiple metabolites in important physiological pathways with robust associations for risk of CHD in women were identified and replicated. These results may offer insights into biological mechanisms of CHD as well as identify potential markers of risk.

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An Investigation Into the Personal Interaction Items Which Best Explain the Variation in Trust Within Automotive Supply Chains

International Journal of Information Systems and Supply Chain Management ◽

10.4018/ijisscm.2018040105 ◽

2018 ◽

Vol 11 (2) ◽

pp. 77-91

Author(s):

Aletta Sophia Tolmay

Keyword(s):

Supply Chains ◽

Customer Value ◽

Tier 2 ◽

Automotive Component ◽

Global Challenges ◽

Personal Interaction ◽

Tier 1 ◽

Automotive Supply ◽

Insight Into ◽

Perceived Customer Value

The sustainability of automotive component suppliers is under threat due to various global challenges. Literature suggests that only the actual personal relationship can differentiate suppliers within supply chains. Literature further encourages more insight into the conceptualization of personal interaction and trust within supply chains. This paper reports on research that tested the importance of trust and its directional linear relationship with personal interaction. Personal interaction revealed a significant correlation with trust, indicating that actions of the Tier 2 supplier during the sourcing process can substantially influence trust with the Tier 1 buyer. It is accordingly crucial for automotive component suppliers to invest in strategies to increase their personal interaction with their buyers in order to promote trust and in turn to promote perceived customer value and customer retention.

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