Biomedical subjects

D Wodarz

Publications and source records attributed to D Wodarz.

34 records · Page 2Linked to original sources

PubMed2000

Direct quantitation of rapid elimination of viral antigen-positive lymphocytes by antiviral CD8(+) T cells in vivo.

Lysis of infected cells by CD8(+) T cells is an important mechanism for the control of virus infections, but remains difficult to quantify in vivo. Here, we study the elimination kinetics of viral antigen-positive lymphocytes by antiviral CD8(+) T cells using flow cytometry and mathematical analysis. In mice acutely infected with lymphocytic choriomeningitis virus, more than 99.99 % of target cells were eliminated each day, corresponding to a half-life of 1.4 h. Even in mice exposed to virus 300 days previously, and with no ex vivo killing activity, 84 % of the target cells were eliminated per day. Unexpectedly, the elimination kinetics of antigen-positive lymphocytes was not significantly impaired in mice deficient in either perforin-, CD95 ligand- or TNF-mediated cytotoxicity. For viruses with a particular tropism for lymphocytes, such as Epstein-Barr virus or HIV, our results illustrate how effectively CD8(+) T cell-mediated elimination of target cells can potentially contribute to virus control and immunosuppression.

Animals↗

PubMed2000

CD8 memory, immunodominance, and antigenic escape.

Previous theoretical work has suggested that efficient virus control or clearance requires antigen-independent persistence of memory cytotoxic T lymphocyte precursors (CTLp), and that failure to generate such memory CTLp can result in persistent infection and eventual loss of virus control. Here we use mathematical models to investigate the relationship between virus control, the clonal composition of the CTL response and the chance of the virus to evolve antigenic escape. In the presence of efficient memory CTLp, virus is controlled at very low levels by a broad CTL response directed against multiple epitopes. In this case, antigenic escape of the virus population is expected to take a very long time. On the other hand, if the CTL response is short lived in the absence of antigen, virus replicates at higher levels and is only opposed by a narrow CTL response, characterized by an immunodominant CTL clone. In this case, antigenic escape is expected to evolve in a short period of time, resulting in progressive loss of virus control. We discuss our findings in relation to data from HIV-1-infected patients.

Epitopes↗

PubMed2000

Evolutionary dynamics of HTLV-I.

Using mathematical models to describe the in vivo dynamics of HTLV-I infection, an explanation is offered for the slow rate of evolution of HTLV-I relative to HIV-1. In agreement with experimental findings, it is assumed that cell activation is required for successful replication in T helper cells and that HTLV-I induces a significant degree of bystander activation. It is found that the rate of evolution of HTLV-I is limited by the restricted availability of activated uninfected T cells, both at high and low proviral loads. This limits the within-host sequence diversity of HTLV-I and may therefore account for the slow rate of evolution of the virus in the population. Specific differences in the in vivo dynamics of HTLV-I and HIV-1 are identified which may account for the discrepancy in the rate of evolution of these two retroviruses.

Evolution, Molecular↗

PubMed2000

The role of antigen-independent persistence of memory cytotoxic T lymphocytes.

We use mathematical models to analyze the role of a memory cytotoxic T lymphocyte (CTL) response in viral infections. The model predicts that antigen-independent persistence of an elevated number of precursor CTL (CTLp) does not protect the host from clinical symptoms upon re-infection. Instead, we find that antigen-independent long-term persistence of CTLp is required to clear virus infections. This mechanism also applies to infection in hosts that have never experienced the pathogen before. Requirement of antigen for the long-term maintenance of CTLp results in failure to clear the infection, even in hosts characterized by a high CTL responsiveness. We compare the CTL model to a B cell model. In keeping with experimentally established findings, B cells are efficient in protecting against re-infection, but are unlikely to clear viral infections unless the virus is cytopathic. We conclude that the role of 'memory CTLp' is different from the role of memory B cells in viral infections: antigen-independent long-term persistence of CTLp is a pre-requisite to ensure clearance of infection.

Animals↗

PubMed2000

Persistent virus infection despite chronic cytotoxic T-lymphocyte activation in gamma interferon-deficient mice infected with lymphocytic choriomeningitis virus.

The role of gamma interferon (IFN-gamma) in the permanent control of infection with a noncytopathic virus was studied by comparing immune responses in wild-type and IFN-gamma-deficient (IFN-gamma -/-) mice infected with a slowly invasive strain of lymphocytic choriomeningitis virus (LCMV Armstrong). While wild-type mice rapidly cleared the infection, IFN-gamma -/- mice became chronically infected. Virus persistence in the latter mice did not reflect failure to generate cytotoxic T-lymphocyte (CTL) effectors, as an unimpaired primary CTL response was observed. Furthermore, while ex vivo CTL activity gradually declined in wild-type mice, long-standing cytolytic activity was demonstrated in IFN-gamma -/- mice. The prolonged effector phase in infected IFN-gamma -/- mice was associated with elevated numbers of CD8(+) T cells. Moreover, a higher proportion of these cells retained an activated phenotype and was actively cycling. However, despite the increased CD8(+) T-cell turnover, which might have resulted in depletion of the memory CTL precursor pool, no evidence for exhaustion was observed. In fact, at 3 months postinfection we detected higher numbers of LCMV-specific CTL precursors in IFN-gamma -/- mice than in wild-type mice. These findings indicate that in the absence of IFN-gamma, CTLs cannot clear the infection and are kept permanently activated by the continuous presence of live virus, resulting in a delicate new balance between viral load and immunity. This interpretation of our findings is supported by mathematical modeling describing the effect of eliminating IFN-gamma-mediated antiviral activity on the dynamics between virus replication and CTL activity.

Animals↗

PubMed2000

Containment of simian immunodeficiency virus infection: cellular immune responses and protection from rechallenge following transient postinoculation antiretroviral treatment.

To better understand the viral and host factors involved in the establishment of persistent productive infection by primate lentiviruses, we varied the time of initiation and duration of postinoculation antiretroviral treatment with tenofovir (9-[2-(R)-(phosphonomethoxy)propyl]adenine) while performing intensive virologic and immunologic monitoring in rhesus macaques, inoculated intravenously with simian immunodeficiency virus SIVsmE660. Postinoculation treatment did not block the initial infection, but we identified treatment regimens that prevented the establishment of persistent productive infection, as judged by the absence of measurable plasma viremia following drug discontinuation. While immune responses were heterogeneous, animals in which treatment resulted in prevention of persistent productive infection showed a higher frequency and higher levels of SIV-specific lymphocyte proliferative responses during the treatment period compared to control animals, despite the absence of either detectable plasma viremia or seroconversion. Animals protected from the initial establishment of persistent productive infection were also relatively or completely protected from subsequent homologous rechallenge. Even postinoculation treatment regimens that did not prevent establishment of persistent infection resulted in downmodulation of the level of plasma viremia following treatment cessation, compared to the viremia seen in untreated control animals, animals treated with regimens known to be ineffective, or the cumulative experience with the natural history of plasma viremia following infection with SIVsmE660. The results suggest that the host may be able to effectively control SIV infection if the initial exposure occurs under favorable conditions of low viral burden and in the absence of ongoing high level cytopathic infection of responding cells. These findings may be particularly important in relation to prospects for control of primate lentiviruses in the settings of both prophylactic and therapeutic vaccination for prevention of AIDS.

Adenine↗

PubMed1999

Specific therapy regimes could lead to long-term immunological control of HIV.

We use mathematical models to study the relationship between HIV and the immune system during the natural course of infection and in the context of different antiviral treatment regimes. The models suggest that an efficient cytotoxic T lymphocyte (CTL) memory response is required to control the virus. We define CTL memory as long-term persistence of CTL precursors in the absence of antigen. Infection and depletion of CD4(+) T helper cells interfere with CTL memory generation, resulting in persistent viral replication and disease progression. We find that antiviral drug therapy during primary infection can enable the development of CTL memory. In chronically infected patients, specific treatment schedules, either including deliberate drug holidays or antigenic boosts of the immune system, can lead to a re-establishment of CTL memory. Whether such treatment regimes would lead to long-term immunologic control deserves investigation under carefully controlled conditions.

CD4-Positive T-Lymphocytes↗

PubMed1999

Dynamics of immune escape in HIV infection.

The dynamics between pathogens and the immune system involve complicated interactions of many different components and this makes the use of mathematical models necessary to provide a correct interpretation of empirical results as well as to generate new insights and hypotheses. We demonstrate this approach by discussing mathematical models describing the dynamics between HIV and the immune response. Specifically, we show that viral evolution towards increased antigenic diversity may be the driving force underlying HIV disease progression and the reason for the eventual breakdown of the immune system upon development of AIDS. Such insights have important implications for designing efficient treatment regimes for HIV-infected patients.

Acquired Immunodeficiency Syndrome↗

PubMed1999

Genetic control and dynamics of the cellular immune response to the human T-cell leukaemia virus, HTLV-I.

About 1% of people infected with the human T-cell leukaemia virus, type 1 (HTLV-I) develop a disabling chronic inflammatory disease of the central nervous system known as HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Patients with HAM/TSP have a vigorous immune response to HTLV-I, and it has been widely suggested that this immune response, particularly the HTLV-I-specific cytotoxic T-lymphocyte (CTL) response, causes the tissue damage that is seen in HAM/TSP. In this paper we summarize recent evidence that a strong CTL response to HTLV-I does in fact protect against HAM/TSP by reducing the proviral load of HTLV-I. We conclude that HTLV-I is persistently replicating at a high level, despite the relative constancy of its genome sequence. These results imply that antiretroviral drugs could reduce the risk of HAM/TSP by reducing the viral load, and that an effective anti-HTLV-I vaccine should elicit a strong CTL response to the virus. The dynamic nature of the infection also has implications for the epidemiology and the evolution of HTLV-I.

Human T-lymphotropic virus 1↗

PubMed1999

Dynamics of macrophage and T cell infection by HIV.

We analyse mathematical models comparing the in vivo dynamics of macrophage- and T cell infection by HIV. Experiments suggest that HIV can only replicate in activated T cells whereas cell activation may not be required for successful replication in macrophages. These assumptions lead to fundamentally different conditions required to establish a persistent infection in the two cell types. While persistent replication in macrophages is achieved if the basic reproductive ratio of the virus, R0, exceeds unity, the establishment of T cell infection may depend on a complex balance between host and viral parameters as well as initial conditions. More specifically, the replication rate of HIV needs to lie above a threshold level and the immune responsiveness of the host below a certain threshold for persistent T cell infection to be possible. In addition, initial virus load has to be intermediate and the initial abundance of CTLs low. Mathematical models predict that macrophage infection may be essential for the successful establishment of HIV in the primary phase of the infection. Acting as a reservoir, they allow the virus to evolve towards increased replication kinetics as well as away from immune recognition, thus paving the way for the rise of exclusively T cell tropic strains using the CXCR4-coreceptor.

CD4-Positive T-Lymphocytes↗

PubMed1999

The dynamics of HTLV-I and the CTL response.

Dominik Wodarz and colleagues describe a mathematical model for the in vivo dynamics of human T-cell leukaemia virus type 1 (HTLV-I) infection and the virus-specific cytotoxic T lymphocyte response. They show that a high rate of viral replication is consistent with the relative sequence invariance of HTLV-I and might be necessary to maintain a persistent infection.

Antiviral Agents↗

PubMed1999

Evolutionary dynamics of HIV-induced subversion of the immune response.

Human immunodeficiency virus (HIV) disease progression is characterized by a slow but steady decline in the number of CD4+ T cells. It results in the development of AIDS when the immune response collapses and the virus grows uncontrolled. Pathogenicity of HIV may be due to viral escape from cellular immune responses as well as virus-induced immune impairment. Here we discuss how the dynamic interactions between the virus population and the immune response may lead to the development of AIDS. In particular we argue that in vivo evolution of HIV may be the driving force successively weakening the immune system. This may lead to increased levels of viraemia as well as to the evolution of more virulent phenotypes which indicate progression to AIDS. These insights are important for understanding the disease process itself and for designing effective treatment regimes.

HIV Infections↗

PubMed1998

The effect of different immune responses on the evolution of virulent CXCR4-tropic HIV.

We use mathematical models to determine possible mechanisms contributing to the evolution and rise of virulent CXCR4-tropic HIV in vivo. The models predict that the ability of the virus to specialize on a given target cell type depends on the exact fitness landscape of the viral mutants. Because this fitness landscape varies between people, this may explain why the evolution of fully CXCR4-tropic strains only occurs in about 50% of infected patients. Assuming that CXCR4-tropic HIV may evolve, we investigate the effect of different immune responses on the rise of such virulent strains. If we assume that CXCR4-tropic HIV is more cytopathic than CCR5-tropic virus, virulent CXCR4-tropic mutants remain suppressed at low levels both in the absence of an immune response, and in the presence of responses that act on the virus before integration into the host genome. On the other hand, this difference in cytopathogenicity is reduced by the presence of immune responses acting on infected cells, allowing CXCR4-tropic HIV to coexist with the CCR5-tropic virus. These results may help to interpret experimental data and are discussed with reference to the literature.

HIV↗

PubMed1998

Virus dynamics: the effect of target cell limitation and immune responses on virus evolution.

Earlier models of virus evolution during single infections do not include target cell limitation. Here we extend the basic mathematical framework of these theories and study the effect of target cell limitation on the evolution of antigenic variation, increasing replication rates and increasing virus load. We find that target cell limitation provides a selection pressure against antigenic diversification, and can therefore provide a limit to diversity. Antigenic diversity increases virus load; at the maximum level of antigenic diversity, virus load, too, is at a maximum.

Antigenic Variation↗

PubMed1998

Dynamics of cytotoxic T-lymphocyte exhaustion.

We examine simple mathematical models to investigate the circumstances under which the dynamics of cytotoxic T-lymphocyte (CTL) activation and differentiation may result in the loss of virus specific CD8+ cells, a process known as CTL exhaustion. We distinguish between two general classes of viruses: (i) viruses infecting cells that are not involved in the immune response; and (ii) viruses infecting antigen presenting cells (APCs) and helper cells. The models specify host and viral properties that lead to CTL exhaustion and indicate that this phenomenon is only likely to be observed with viruses infecting APCs and helper cells. Moreover, it is found that for such viruses, a high rate of replication and a low degree of cytopathogenicity promote the exhaustion of the CTL response. In addition, a high initial virus load and a low CD4+ cell count promote the occurrence of CTL exhaustion. These conclusions are discussed with reference to empirical data on lymphocytic choriomeningitis virus and on human immunodeficiency virus.

HIV↗

PubMedDate not supplied

Genetic instability and the evolution of angiogenic tumor cell lines (review).

Advanced tumor growth requires the formation of new blood vessels (angiogenesis). Whether new blood vessels are formed or not depends on a balance between angiogenesis inhibitors and promoters. Host tissue, as well as tumor cells, express inhibitory factors preventing angiogenesis. During cancer progression, tumor cell lines evolve which produce factors promoting the angiogenic switch. We use mathematical models in order to examine the conditions required for angiogenic cell lines to emerge and hence for the disease to progress. We find that genetic instability, defined as a much elevated mutation rate of somatic cells, is required for the emergence of angiogenic tumor cells. This is because a high mutation rate ensures that within a short period of time, a sufficiently high number of angiogenic cells are generated. This founder population of mutant cells is large enough to overcome the inhibitory factors produced by the tissue thereby inducing the angiogenic switch through the production of promoters. In the absence of genetic instability, angiogenic cells cannot fix, even if the relevant mutations are generated at low levels in the tumor cell population. This is because angiogenic promoters will not be sufficiently abundant to counter the influence of inhibitory factors. In this context, the inhibition of angiogenesis can be viewed as a host defense ensuring that the tumor need be genetically unstable if it is to grow and progress beyond a certain size limit. We observe that genetic instability is of value early in tumorigenesis but becomes a liability later. This is because instability decreases the fitness of the angiogenic tumor once it has become established.

Animals↗