Induction of appropriate Th-cell phenotypes: cellular decision-making in heterogeneous environments.

Helper T (Th)-cell differentiation is a key event in the development of the adaptive immune response. By the production of a range of cytokines, Th cells determine the type of immune response that is raised against an invading pathogen. Th cells can adopt many different phenotypes, and Th-cell phenotype decision-making is crucial in mounting effective host responses. This review discusses the different Th-cell phenotypes that have been identified and how Th cells adopt a particular phenotype. The regulation of Th-cell phenotypes has been studied extensively using mathematical models, which have explored the role of regulatory mechanisms such as autocrine cytokine signalling and cross-inhibition between self-activating transcription factors. At the single cell level, Th responses tend to be heterogeneous, but corrections can be made soon after T-cell activation. Although pathogens and the innate immune system provide signals that direct the induction of Th-cell phenotypes, these instructive mechanisms could be easily subverted by pathogens. We discuss that a model of success-driven feedback would select the most appropriate phenotype for clearing a pathogen. Given the heterogeneity in the induction phase of the Th response, such a success-driven feedback loop would allow the selection of effective Th-cell phenotypes while terminating incorrect responses.

Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proliferation.

The origin of CD4+ T cells reappearing in the blood following antiretroviral therapy in human immunodeficiency virus type-1 (HIV-1) infection is still controversial. Here we show, using mathematical modeling, that redistribution of T cells to the blood can explain the striking correlation between the initial CD4+ and CD8+ memory T-cell repopulation and the observation that 3 weeks after the start of treatment memory CD4+ T-cell numbers reach a plateau. The increase in CD4+ T cells following therapy most likely is a composite of initial redistribution, accompanied by a continuous slow repopulation with newly produced naive T cells.

Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection.

Recent thymic emigrants can be identified by T cell receptor excision circles (TRECs) formed during T-cell receptor rearrangement. Decreasing numbers of TRECs have been observed with aging and in human immunodeficiency virus (HIV)-1 infected individuals, suggesting thymic impairment. Here, we show that in healthy individuals, declining thymic output will affect the TREC content only when accompanied by naive T-cell division. The rapid decline in TRECs observed during HIV-1 infection and the increase following HAART are better explained not by thymic impairment, but by changes in peripheral T-cell division rates. Our data indicate that TREC content in healthy individuals is only indirectly related to thymic output, and in HIV-1 infection is mainly affected by immune activation.

Limited CD4+ T-cell renewal in early HIV-1 infection: effect of highly active antiretroviral therapy.

We show that the fraction of proliferating CD4+ lymphocytes is similar in HIV-infected subjects in the early stage of disease and in HIV-negative subjects, whereas the fraction of proliferating CD8+ lymphocytes is increased 6.8-fold in HIV-infected subjects. After initiation of antiviral therapy, there is a late increase in proliferating CD4+ T cells associated with the restoration of CD4+ T-cell counts. These results provide strong support for the idea of limited CD4+ T-cell renewal in the early stage of HIV infection and indicate that after effective suppression of virus replication, the mechanisms of CD4+ T-cell production are still functional in early HIV infection.

Translation initiation factor eIF2Bε promotes Wnt-mediated clonogenicity and global translation in intestinal epithelial cells.

Modulation of global mRNA translation, which is essential for intestinal stem cell function, is controlled by Wnt signaling. Loss of tumor supressor APC in stem cells drives adenoma formation through hyperactivion of Wnt signaling and dysregulated translational control. It is unclear whether factors that coordinate global translation in the intestinal epithelium are needed for APC-driven malignant transformation. Here we identified nucleotide exchange factor eIF2Bε as a translation initiation factor involved in Wnt-mediated intestinal epithelial stemness. Using eIF2BεArg191His mice with a homozygous point mutation that leads to dysfunction in the enzymatic activity, we demonstrate that eIF2Bε is involved in small intestinal crypt formation, stemness marker expression, and secreted Paneth cell-derived granule formation. Wnt hyperactivation in ex vivo eIF2BεArg191His organoids, using a GSK3ß inhibitor to mimic Apc driven transformation, shows that eIF2Bε is essential for Wnt-mediated clonogenicity and associated increase of the global translational capacity. Finally, we observe high eIF2Bε expression in human colonic adenoma tissues, exposing eIF2Bε as a potential target of CRC stem cells with aberrant Wnt signaling.

Predicting the duration of antiviral treatment needed to suppress plasma HIV-1 RNA.

Effective therapeutic interventions and clinical care of adults infected with HIV-1 require an understanding of factors that influence time of response to antiretroviral therapy. We have studied a cohort of 118 HIV-1-infected subjects naive to antiretroviral therapy and have correlated the time of response to treatment with a series of virological and immunological measures, including levels of viral load in blood and lymph node, percent of CD4 T cells in lymph nodes, and CD4 T-cell count in blood at study entry. Suppression of viremia below the limit of detection, 50 HIV-1 RNA copies/mL of plasma, served as a benchmark for a successful virological response. We employed these correlations to predict the length of treatment required to attain a virological response in each patient. Baseline plasma viremia emerged as the factor most tightly correlated with the duration of treatment required, allowing us to estimate the required time as a function of this one measure.

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A 4-week-old girl presented with annular skin lesions caused by neonatal lupus syndrome.

Overshoot of HIV-1 viraemia after early discontinuation of antiretroviral treatment.

OBJECTIVE: To determine whether, as predicted by predator-prey dynamics, early withdrawal of antiretroviral therapy, i.e. when the number of CD4+ lymphocytes is still elevated, results in an overshoot of HIV-1 viraemia due to infection of increased numbers of available target cells at that time. DESIGN AND METHODS: Five HIV-1-infected individuals were identified who discontinued antiretroviral therapy for various reasons after 8-19 days, and from whom stored serum samples obtained before, during, and shortly after treatment were available for measurement of HIV-1 RNA load. A mathematical model was designed to assess whether increased target cell availability could quantitatively explain the clinical observations. RESULTS: After therapy withdrawal, increases in the HIV-1 RNA load to levels exceeding pretreatment values by log10 0.6-1.5 copies/ml were observed after 2-17 days in all four of the individuals who had treatment-induced increases in CD4+ cell counts at the time of therapy withdrawal. Increases in viraemia were maximal within a few days, and subsequently seemed to wane until the pretreatment equilibrium between virus and its target cells was attained. Mathematical modelling confirms that these transient increases in viraemia can be explained by increased availability of target cells at the time of therapy withdrawal. CONCLUSIONS: Transient rises in HIV-1 viraemia do occur following early therapy withdrawal. These rises especially warrant consideration in short-term antiretroviral regimens for prevention of mother-to-child transmission, as are being studied in developing countries, since they could result in an increased transmission risk during the post-partum period through breast-feeding. This possibility needs to be investigated urgently.

A minimal model for T-cell vaccination.

We have developed a mathematical model for the regulation of the growth of autoreactive T cells (the T cells responsible for autoimmunity). The model is very simple in that it is based only on the fundamental properties of T cells. However, despite this simplicity, it can account for a variety of phenomena referred to as T-cell vaccination. The purpose of T-cell vaccination is to create resistance to autoimmunity. This can be achieved by injecting either a subpathogenic quantity of autoreactive T cells, or attenuated autoreactive cells, or cells that recognize the autoreactive cells. The results of our model are based on the assumption that the self antigens involved in T-cell vaccination are normally not expressed; thus the autoreactive T lymphocytes are neither activated nor negatively selected. Self tolerance, therefore, corresponds to a 'passive' state. T-cell vaccination induces a transition from this passive state of tolerance to an active state of tolerance. In this state the autoreactive cells are controlled by regulator cells which recognize the autoreactive cells. The model predicts a qualitative difference between vaccination with normal autoreactive cells and vaccination with attenuated autoreactive cells. Normal cells may give rise to a permanent switch to the vaccinated state; attenuated cells, however, can provide only transient protection, which is dose dependent. Preliminary experimental data confirm this prediction. Finally, we propose a speculative explanation for relapsing autoimmune disease.

Anti-CD4 therapy for AIDS suggested by mathematical models.

HIV-1 infection typically involves a long clinical latency stage during which CD4 counts decline slowly. For the later part of the clinical latency stage it was found recently that this is a highly dynamic phase characterized by rapid turnover rates. Clinical latency can therefore be considered as a quasi-equilibrium state in which CD4 and HIV-1 turnover are in almost perfect balance. Here we consider this quasi-equilibrium to be the stable steady state of a simple host-parasite model in which the parasite (HIV-1) level is determined by the availability of infectable hosts (activated CD4+ T cells). Such models adequately account for the clinical data on the evolution of drug resistant mutants appearing after the administration of anti-HIV drugs. The model suggests a novel therapeutic approach for AIDS: reducing the CD4 count slightly will strongly reduce the HIV load. Combining this anti-CD4 treatment with conventional anti-HIV therapy would prevent the outgrowth of drug resistant mutants.

How diverse should the immune system be?

We develop a probability-based model that suggests a novel explanation for the enormous diversity of the lymphocyte repertoire in the immune system. Taking into account the fraction of the repertoire that is expected to be rendered tolerant because of potential self reactivity, we calculated PE, the probability that a pathogen escapes recognition by the immune system. Obviously, for PE to be low the diversity should be large. Our novel result is that the major factor in this relation between diversity and PE is formed by the number of self antigens. Thus our model suggests that, rather than the number of foreign antigens the system is protecting against, the diversity reflects the number of self antigens the immune system needs to avoid reactivity with.

Small variations in multiple parameters account for wide variations in HIV-1 set-points: a novel modelling approach.

Steady-state levels of HIV-1 viraemia in the plasma vary more than a 1,000-fold between HIV-positive patients and are thought to be influenced by several different host and viral factors such as host target cell availability, host anti-HIV immune response and the virulence of the virus. Previous mathematical models have taken the form of classical ecological food-chain models and are unable to account for this multifactorial nature of the disease. These models suggest that the steady-state viral load (i.e. the set-point) is determined by immune response parameters only. We have devised a generalized consensus model in which the conventional parameters are replaced by so-called 'process functions'. This very general approach yields results that are insensitive to the precise form of the mathematical model. Here we applied the approach to HIV-1 infections by estimating the steady-state values of several process functions from published patient data. Importantly, these estimates are generic because they are independent of the precise form of the underlying processes. We recorded the variation in the estimated steady-state values of the process functions in a group of HIV-1 patients. We developed a novel model by providing explicit expressions for the process functions having the highest patient-to-patient variation in their estimated values. Small variations from patient to patient for several parameters of the new model collectively accounted for the large variations observed in the steady-state viral burden. The novel model remains in full agreement with previous models and data.

The race between initial T-helper expansion and virus growth upon HIV infection influences polyclonality of the response and viral set-point.

Infection with HIV is characterized by very diverse disease-progression patterns across patients, associated with a wide variation in viral set-points. Progression is a multifactorial process, but an important role has been attributed to the HIV-specific T-cell response. To explore the conditions under which different set-points may be explained by differences in initial CD4 and CD8 T-cell responses and virus inoculum, we have formulated a model assuming that HIV-specific CD4 cells are both targets for infection and mediators of a monoclonal or polyclonal immune response. Clones differ in functional avidity for HIV epitopes. Importantly, in contrast to previous models, in this model we obtained coexistence of multiple clones at steady-state viral set-point, as seen in HIV infection. We found that, for certain parameter conditions, multiple steady states are possible: with few initial CD4 helper cells and high virus inoculum, no immune response is established and target-cell-limited infection follows, with associated high viral load; when CD4 clones are initially large and virus inoculum is low, infection can be controlled by several clones. The conditions for the dependence of viral set-point on initial inoculum and CD4 T-helper clone availability are investigated in terms of the effector mechanism of the clones involved.

Poor repertoire selection in symmetric idiotypic network models.

The selection of B and T cell repertoires is known to be influence by idiotypic interactions during early ontogeny. Early B cell clones are multi-specific, have numerous idiotypic interactions, produce IgM antibodies, and may constitute a separate cell lineage (characterised by the Ly1 or CD5 marker). Furthermore, because early B cells are self-reactive, self antigens should play a crucial role in the repertoire selection. Previously we developed a theoretical model of idiotypic B cell interactions. The model is based on a (symmetric) bell-shaped interaction function. The symmetry and the shape are a consequence of the process of receptor crosslinking. Assuming that early (i.e. IgM) B cell interactions are independent of helper T cell activation, we now apply this model to the problem of idiotypic repertoire selection. In the model the molecular structures of B cell receptors (i.e. of the idiotypes) and of self antigens are represented by random (bit)patterns. Interactions are based on complementary matches between these patterns. Therefore, the repertoire selection is brought about by stimulatory networks based upon complementary matches. These results show that the presence of a self antigen specifically shapes the B cell repertoire. The selection depends on the nature of the antigenic signal; we incorporate either stimulatory or inhibitory (i.e. tolerizing) self antigens. Clones stimulated by the self antigen tend to become aggressive in the network; tolerized self-reactive clones tend to become suppressed. Thus, idiotypic interactions play a facilitating role in self/non-self discrimination. However, since the idiotypic selection is only a tendency, the immune system should not rely on it. We next incorporate two classes of B cells. We call them the early, or "IgM", and the late, or "IgG", B cells (IgG B cells appear after the development of the IgM repertoire). IgG B cells may have only a few idiotypic interactions. We investigate whether the early IgM repertoire, which is (partly) selected by self antigen, influences the selection of the late IgG repertoire. It turns out that this influence can only be non-specific. Either we find a similar tendency in the IgG repertoire, or we find that the IgG repertoire influences the IgM repertoire non-specifically. Thus, despite the fact that this theoretical work readily confirms empirical results showing that the manipulation of early idiotypic interactions can have specific and long-lasting effects, the presupposed physiological role of these interactions, in terms of self-reactivity or repertoire selection, fails to develop in our models.

Normal telomere lengths in naive and memory CD4+ T cells in HIV type 1 infection: a mathematical interpretation.

To study CD4+ T cell productivity during HIV-1 infection, CD4+ T cell telomere lengths were measured. Cross-sectional and longitudinal analysis of HIV-1-infected individuals with CD4+ T cells counts >300 cells/mm3 showed normal average telomeric restriction fragment (TRF) length and normal shortening rates of CD45RA+ naive and CD45RO+ memory CD4+ T cells. These TRF data were interpreted in terms of CD4+ T cell production by means of a mathematical model. This model resolves previous criticisms arguing that the normal TRF length of CD4+ T cells in HIV-1 clinical latency is due to the killing of dividing CD4+ T cells by the virus. Only an increased priming rate of naive CD4+ T cells to become memory cells may elongate the average TRF length of memory CD4+ T cells, and may therefore mask the shortening effect of increased turnover in the CD4+ memory T cell compartment. The data are more compatible with the notion that during HIV-1 clinical latency the turnover of CD4+ T cells is not markedly increased, however, and that HIV-related interference with renewal from progenitors plays a role in CD4+ T cell depletion. In such a "limited renewal" scenario disease progression is no longer a consequence of markedly increased CD4+ T cell production.

Selection by AZT and rapid replacement in the absence of drugs of HIV type 1 resistant to multiple nucleoside analogs.

We studied the intrahost evolution and dynamics of a multidrug-resistant HIV-1, which contains an insertion of two amino acids (aa) and several aa changes within the reverse transcriptase (RT) gene. From an individual receiving intermittent therapy, sequences of 231 full-length molecular clones of HIV-1 RT were obtained from serum-derived viruses at 12 consecutive time points over a period of 6 years, 17 to 20 clones per time point. In the 3.5-year period prior to the first course of therapy, only wild-type (wt) viruses were found. As soon as 6 months after the start of zidovudine (AZT) monotherapy, all viruses contained an insertion of two aa between positions 68 and 69 of the RT and aa changes at positions 67 and 215, a combination conferring resistance to multiple nucleoside analogs. After termination of therapy, the insertion mutants were rapidly and completely replaced by the wt viruses. In turn, the insertion mutants replaced the wt viruses after initiation of therapy with 3TC, d4T, and saquinavir. After termination of triple therapy, the wt viruses completely replaced the mutants within 1 month, which is markedly faster than has been observed earlier for the replacement of AZT-resistant viruses. Fast replacements of the mutant virus populations after termination of therapy indicate gross competitive disadvantage of the insertion mutant in the absence of therapy, which we estimated by using several models. The insertion mutants attained high virus loads, demonstrating that virus load cannot be used as a direct measure of virus fitness.

Mathematical models of human CD4+ T-cell population kinetics.

We review how mathematical models help the interpretation of data measuring CD4+ T-cell kinetics by two recently-developed techniques. Mathematical models are developed for the average content of T-cell receptor excision circles (TRECs) and the average telomeric restriction fragment (TRF) in T-cells in the peripheral blood. Changes in the TRECs were supposed to indicate changes in thymic production. The rate at which naive and memory CD4+ T-cells erode their telomeres was supposed to reflect their respective division rates. Analysing the mathematical models, we show that rapid changes in the TRECs per naive T-cell are most likely due to changes in the division rates, and that the rates of telomere erosion fail to reflect naive and memory division rates. The model is applied to explain data showing that rheumatoid arthritis (RA) patients have abnormal TRECs and telomeres.

Recent developments in idiotypic network theory.

A recent class of mathematical models of the immune network is reviewed. The models in this class are based upon the bell-shaped activation function that is known to be characteristic for receptor cross-linking. These network models have a large number of self-regulatory properties. This review discusses of number of these properties, i.e. immunological memory, suppression, and repertoire selection.

Quantifying how MHC polymorphism prevents pathogens from adapting to the antigen presentation pathway.

The classical antigen presentation pathway consists of two monomorphic (proteasome and TAP) and one polymorphic components (MHC Class I). Viruses can escape CTL responses by mutating an epitope so that it is no longer correctly processed by the pathway. Whereas escape mutations that affect MHC binding are typically no longer under selection pressure in the next host of the virus (as hosts differ in their MHC alleles), escape mutations that affect the antigen processing of epitope precursors prevent the use of those epitope precursors by any of the MHC alleles in a host population. Viruses might therefore be under selection pressure to adapt to the monomorphic proteasome and TAP. We designed an agent-based model of a host population, in which an HIV-1 like virus adapts to the antigen presentation pathway of individual hosts, as the virus spreads through the population. We studied how the polymorphism of the MHC and the monomorphism of the proteasome and TAP affected the level of adaptation to the host population that the virus could reach. We found that due to the polymorphism and high specificity of the MHC class I molecules, the CTL epitopes that are targeted by the CTL responses of different hosts do not share many epitope precursors. Therefore, escape mutations in epitope precursors are frequently released from immune selection pressure, and can revert back to the virus wildtype sequence. As a result, the selection pressure on the virus to adapt to the proteasome and TAP is relatively small, which explains the low level of adaptation of the virus to the monomorphic steps in the antigen presentation pathway.