Claus Kadelka

• Doctor of Philosophy
• Professor (Assistant) at Iowa State University

Broadly neutralizing antibodies (bnAbs) are a focal component of HIV-1 vaccine design, yet basic aspects of their induction remain poorly understood. Here we report on viral, host and disease factors that steer bnAb evolution using the results of a systematic survey in 4,484 HIV-1-infected individuals that identified 239 bnAb inducers. We show that...

A hallmark of HIV-1 infection is the continuously declining number of the virus’ predominant target cells, activated CD4⁺ T cells. With diminishing CD4⁺ T cell levels, the capacity to utilize alternate cell types and receptors, including cells that express low CD4 receptor levels such as macrophages, thus becomes crucial. To explore evolutionary pa...

Time- and state-discrete dynamical systems are frequently used to model molecular networks. This paper provides a collection of mathematical and computational tools for the study of robustness in Boolean network models. The focus is on networks governed by $k$-canalizing functions, a recently introduced class of Boolean functions that contains the...

The concept of a nested canalizing Boolean function has been studied over the last decade in the context of understanding the regulatory logic of molecular interaction networks, such as gene regulatory networks. Such networks are predominantly governed by nested canalizing functions. Derrida values are frequently used to analyze the robustness of a...

The global dynamics of gene regulatory networks are known to show robustness to perturbations in the form of intrinsic and extrinsic noise, as well as mutations of individual genes. One molecular mechanism underlying this robustness has been identified as the action of so-called microRNAs that operate via feedforward loops. We present results of a...

The inference of gene regulatory networks (GRNs) from high-throughput data constitutes a fundamental and challenging task in systems biology. Boolean networks are a popular modeling framework to understand the dynamic nature of GRNs. In the absence of reliable methods to infer the regulatory logic of Boolean GRN models, researchers frequently assum...

The recurrence of epidemic waves has been a hallmark of infectious disease outbreaks. Repeated surges in infections pose significant challenges to public health systems, yet the mechanisms that drive these waves remain insufficiently understood. Most prior models attribute epidemic waves to exogenous factors, such as transmission seasonality, viral...

Infectious diseases thrive in war-torn societies. The recent sharp increase in human conflict and war thus requires the development of disease mitigation tools that account for the specifics of war, such as the scarcity of important public health resources. We developed a compartmental, differential equation-based disease model that considers key s...

Infectious diseases thrive in war-torn societies. The recent sharp increase in human conflict and war thus requires the development of disease mitigation tools that account for the specifics of war, such as scarcity of important public health resources. Differential equation-based compartmental models constitute the standard tool for forecasting di...

Biological networks, such as gene regulatory networks, possess desirable properties. They are more robust and controllable than random networks. This motivates the search for structural and dynamical features that evolution has incorporated into biological networks. A recent meta-analysis of published, expert-curated Boolean biological network mode...

Chickpeas are more sustainable than other food systems and have high a nutritional value, especially regarding their vitamin composition. One of the main vitamins in chickpeas is vitamin B6, which is very important for several human metabolic functions. Since chickpeas are consumed after cooking, our goal was to better understand the role of leachi...

As the world becomes ever more connected, the chance of pandemics increases as well. The recent COVID-19 pandemic and the concurrent global mass vaccine roll-out provides an ideal setting to learn from and refine our understanding of infectious disease models for better future preparedness. In this review, we systematically analyze and categorize m...

As the world becomes ever more connected, the chance of pandemics increases as well. The recent COVID-19 pandemic and the concurrent global mass vaccine roll-out provides an ideal setting to learn from and refine our understanding of infectious disease models for better future preparedness. In this review, we systematically analyze and categorize m...

The concept of control is central to understanding and applications of biological network models. Some of their key structural features relate to control functions, through gene regulation, signaling, or metabolic mechanisms, and computational models need to encode these. Applications of models often focus on model-based control, such as in biomedi...

Gene regulatory networks (GRNs) play a central role in cellular decision-making. Understanding their structure and how it impacts their dynamics constitutes thus a fundamental biological question. GRNs are frequently modeled as Boolean networks, which are intuitive, simple to describe, and can yield qualitative results even when data are sparse. We...

This paper addresses two topics in systems biology, the hypothesis that biological systems are modular and the problem of relating structure and function of biological systems. The focus here is on gene regulatory networks, represented by Boolean network models, a commonly used tool. Most of the research on gene regulatory network modularity has fo...

Contact networks are heterogeneous. People with similar characteristics are more likely to interact, a phenomenon called assortative mixing or homophily. Empirical age-stratified social contact matrices have been derived by extensive survey work. We lack however similar empirical studies that provide social contact matrices for a population stratif...

Boolean functions can be represented in many ways including logical forms, truth tables, and polynomials. Additionally, Boolean functions have different canonical representations such as minimal disjunctive normal forms. Another canonical representation is based on the polynomial representation of Boolean functions and the biologically motivated co...

People are more likely to interact with other people of their ethnicity—a phenomenon known as ethnic homophily. In the United States, people of color are known to hold proportionately more high-contact jobs and are thus more at risk of virus infection. At the same time, these ethnic groups are on average younger than the rest of the population. Thi...

Stability is an important characteristic of network models that has implications for other desirable aspects such as controllability. The stability of a Boolean network depends on various factors, such as the topology of its wiring diagram and the type of the functions describing its dynamics. In this paper, we study the stability of linear Boolean...

Contact networks are heterogeneous. People with similar characteristics are more likely to interact, a phenomenon called assortative mixing or homophily. While age-assortativity is well-established and social contact matrices for populations stratified by age have been derived through extensive survey work, we lack empirical studies that describe c...

This paper presents the foundation for a decomposition theory for Boolean networks, a type of discrete dynamical system that has found a wide range of applications in the life sciences, engineering, and physics. Given a Boolean network satisfying certain conditions, there is a unique collection of subnetworks so that the network can be reconstructe...

Contact between people with similar opinions and characteristics occurs at a higher rate than among other people, a phenomenon known as homophily. The presence of clusters of unvaccinated people has been associated with increased incidence of infectious disease outbreaks despite high population-wide vaccination rates. The epidemiological consequenc...

The V3 loop of the HIV-1 envelope (Env) protein elicits a vigorous, but largely non-neutralizing antibody response directed to the V3-crown, whereas rare broadly neutralizing antibodies (bnAbs) target the V3-base. Challenging this view, we present V3-crown directed broadly neutralizing Designed Ankyrin Repeat Proteins (bnDs) matching the breadth of...

Background Anticipating an initial shortage of vaccines for COVID-19, the Centers for Disease Control (CDC) in the United States developed priority vaccine allocations for specific demographic groups in the population. This study evaluates the performance of the CDC vaccine allocation strategy with respect to multiple potentially competing vaccinat...

Anticipating an initial shortage of vaccines for COVID-19, the Centers for Disease Control (CDC) in the United States developed priority vaccine allocations for specific demographic groups in the population. In this poster, I present our recent study that evaluates the performance of the CDC vaccine allocation strategy with respect to multiple pote...

Background: Anticipating an initial shortage of vaccines for COVID-19, the Centers for Disease Control (CDC) in the United States developed priority vaccine allocations for specific demographic groups in the population. This study evaluates the performance of the CDC vaccine allocation strategy with respect to multiple potentially competing vaccina...

Boolean functions can be represented in many ways including logical forms, truth tables, and polynomials. Additionally, Boolean functions have different canonical representations such as minimal disjunctive normal forms. Other canonical representation is based on the polynomial representation of Boolean functions where they can be written as a nest...

Background: Anticipating an initial shortage of vaccines for COVID-19, the Centers for Disease Control (CDC) in the United States developed priority vaccine allocations for specific demographic groups in the population. This study evaluates the performance of the CDC vaccine allocation strategy with respect to multiple potentially competing vaccina...

Contact between people with similar opinions and characteristics occurs at a higher rate than among other people, a phenomenon known as homophily. The presence of clusters of unvaccinated people has been associated with increased incidence of infectious disease outbreaks despite high vaccination coverage. The epidemiological consequences of homophi...

Gene regulatory networks (GRNs) describe how a collection of genes governs the processes within a cell. Understanding how GRNs manage to consistently perform a particular function constitutes a key question in cell biology. GRNs are frequently modeled as Boolean networks, which are intuitive, simple to describe, and can yield qualitative results ev...

Boolean networks are frequently used to model biological systems, such as gene regulatory networks. Canalizing functions have been suggested as suitable update rules for genetic networks and have been studied rigorously. Mathematically, the biology-inspired concept of canalization means that a single input can determine the output of a function, ir...

We present a stochastic compartmental network model of SARS-CoV-2 and COVID-19 exploring the effects of policy choices in three domains: social distancing, hospital triaging, and testing. We distinguished between high-risk and low-risk members of the population, and modeled differences in social interactions due to context, risk level, infection st...

Background Identifying local outbreaks and their drivers is a key step towards curbing HIV transmission and potentially achieving HIV elimination. Such outbreaks can be identified as transmission clusters extracted from phylogenetic trees constructed of densely sampled viral sequences. In this study, we combined phylogenetic transmission clusters w...

Perturbations in B cells are a hallmark of HIV-1 infection. This is signified by increased numbers of exhausted CD21 neg memory B cells, driven by continuous antigen-specific and bystander activation. Using high-dimensional flow cytometry, we demonstrate that this exhausted phenotype is also prevalent among peripheral antigen-inexperienced naive an...

Purpose of review: Broadly neutralizing antibodies (bnAbs) are considered a key component of an effective HIV-1 vaccine, but despite intensive efforts, induction of bnAbs by vaccination has thus far not been possible. Potent bnAb activity is rare in natural infection and a deeper understanding of factors that promote or limit bnAb evolution is cri...

Objectives Emerging resistance to antiretroviral drugs may jeopardize the achievements of improved access to ART. We compared the prevalence of different resistance mutations in HIV-infected adults with virological failure in a cohort with regular routine viral load (VL) monitoring (Switzerland) and cohorts with limited access to VL testing (Uganda...

Objectives: Emerging resistance to antiretroviral drugs may jeopardize the achievements of improved access to ART. We compared the prevalence of different resistance mutations in HIV-infected adults with virological failure in a cohort with regular routine viral load (VL) monitoring (Switzerland) and cohorts with limited access to VL testing (Ugan...

Age-mixing patterns are of key importance for understanding the dynamics of human immunodeficiency virus (HIV)-epidemics and target public health interventions. We use the densely sampled Swiss HIV Cohort Study (SHCS) resistance database to study the age difference at infection in HIV transmission pairs using phylogenetic methods. In addition, we i...

Understanding the determinants of broadly neutralizing antibody (bNAb) evolution is crucial for the development of bNAb-based HIV vaccines1. Despite emerging information on cofactors that promote bNAb evolution in natural HIV-1 infections, in which the induction of bNAbs is genuinely rare2, information on the impact of the infecting virus strain on...

Understanding pathways that promote HIV-1 broadly neutralizing antibody (bnAb) induction is crucial to advance bnAb-based vaccines. We recently demarcated host, viral, and disease parameters associated with bnAb development in a large HIV-1 cohort screen. By establishing comprehensive antibody signatures based on IgG1, IgG2, and IgG3 activity to 13...

Broadly neutralizing antibodies (bnAbs) to HIV-1 can evolve after years of an iterative process of virus escape and antibody adaptation that HIV-1 vaccine design seeks to mimic. To enable this, properties that render HIV-1 envelopes (Env) capable of eliciting bnAb responses need to be defined. Here, we followed the evolution of the V2 apex directed...

The monitoring and assessment of a broadly neutralizing antibody (bnAb) based HIV-1 vaccine require detailed measurements of HIV-1 binding antibody responses to support the detection of correlates of protection. Here we describe the development of a flexible, high-throughput microsphere based multiplex assay system that allows monitoring complex bi...

The monitoring and assessment of a broadly neutralizing antibody (bnAb) based HIV-1 vaccine require detailed measurements of HIV-1 binding antibody responses to support the detection of correlates of protection. Here we describe the development of a flexible, high-throughput microsphere based multiplex assay system that allows monitoring complex bi...

ELife digest In epidemiology, the “basic reproductive number” describes how efficiently a disease is transmitted, and represents the average number of new infections that an infected individual causes. If this number is less than one, many people do not infect anybody and hence the transmission chains die out. On the other hand, if the basic reprod...

Background Parent-offspring (PO) regression is a central tool to determine the heritability of phenotypic traits; i.e., the relative extent to which those traits are controlled by genetic factors. The applicability of PO regression to viral traits is unclear because the direction of viral transmission—who is the donor (parent) and who is the recipi...

The concept of a nested canalizing Boolean function has been studied over the course of the last decade in the context of understanding the regulatory logic of molecular interaction networks, such as gene regulatory networks. Such functions appear preferentially in published models of such networks. Recently, this concept has been generalized to in...

Overview Env mutation in clones isolated from CD4low and reversion culturing. (TIF)

Comparison of free virus, cell-cell transmission and fusion capacity of CD4low adapted viruses. Data correspond to Fig 3 and depict raw RLU values obtained for the depicted experiments (A) Titration of Env pseudoviruses on TZM-bl and PBMC. Infectivity of CD4low adapted viruses in (B) cell-cell transmission and (C) fusion. (TIF)

Infectivity of CD4low adapted viruses on macrophages. Differentially conditioned monocyte derived macrophage phenotypes and infection. (A) Phenotypic verification of M-MDM and G-MDM preparation by phase contrast morphology and flow cytometry analysis of CD4, CD64 and CD163. Histograms depict one of 2 independent experiments for CD163 and CD64 stain...

Inhibitory activity of CD4 and CCR5 inhibitors against CD4low adapted viruses during free-virus infection and fusion. (TIF)

Estimations of trimer number per virion by quantitative gp120 and p24 ELISA ratios. (TIF)

Differential infection of Affinofile cells with varying CD4 and CCR5 levels by CD4low adapted viruses. 293-T Affinofiles were induced to express forty-two unique combinations of (A) CD4 and (B) CCR5 levels. Receptor levels were assessed by quantitative flow cytometry. Data are from one of two independent experiments. (C) and (D) Infection of Affino...

Statistical analysis of entry kinetics following paired curve fitting. Alternative analysis of transition time between steps of the entry process of the data depicted in Fig 7. Data points from the two replicates from the same experiment were combined (i.e. paired) before fitting the curves and averaging individual T½ values. Estimated time interva...

Comparison of free virus, cell-cell transmission and fusion capacity of patient-matched macrophage tropic and non-macrophage-tropic viruses. Data correspond to Fig 8 and depicts raw RLU values obtained for the (A) titration of Env pseudoviruses on TZM-bl and infectivity of CD4low adapted viruses in (B) cell-cell transmission and (C) fusion. (TIF)

Multi-clade virus panel probed for CD4-DARPin 55.2 sensitivity. (TIF)

Patient isolate pairs of macrophage- and non-macrophage-tropic envelopes. (TIF)

Inhibitors and antibodies. (TIF)

CD4low adaptation panel sequence characteristics. (TIF)

Entry kinetics curve fitting sensitivity analysis. (TIF)

Three dimensional Affinofile infection profiles. Affinofiles were induced to express forty-two unique combinations of CD4 and CCR5 and infected with the indicated Env-pseudoviruses. Data of the CD4low envelope panel shown in S1 Fig and primary virus JR-FL for comparison are depicted. Two independent assays are shown. Axes legends are indicated at t...

Prevalence of key mutations observed upon adaptation to CD4low targets amongst primary viruses recorded in the Los Alamos sequence database. 4907 available Env sequences were analyzed. (TIF)

Time- and state-discrete dynamical systems are frequently used to model molecular networks. This paper provides a collection of mathematical and computational tools for the study of robustness in Boolean network models. The focus is on networks governed by $k$-canalizing functions, a recently introduced class of Boolean functions that contains the...

It has been discovered that gene regulation is a strongly stochastic, yet still robust process. One well-known indicator for the robustness of gene regulatory networks is the so-called Derrida plot. For a fixed number of perturbations, the Derrida value is the expected Hamming distance after one time step. This value is generally small for networks...