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D Wodarz

Publications and source records attributed to D Wodarz.

At least 19 recordsLinked to original sources
PubMed2002

The dual role of CD4 T helper cells in the infection dynamics of HIV and their importance for vaccination.

Given the role of the CD4 T helper cells in the development of memory CTL precursors, it seems beneficial to boost the CD4 T helper response in the context of vaccination against the human immunodeficiency virus (HIV). However, CD4 T cells are also the preferred targets of infection by HIV. Here, we address the question as to whether it is advantageous to stimulate the CD4 T helper cell response, as this will increase the pool of potential target cells of infection. To do so we formulated a mathematical model describing the interactions between virus-infected cells, susceptible cells, HIV-specific CD4 helper T cells, and CTL precursor (CTLp) and effector cells (CTLe). The effect of increased initial CD4 helper and CTLp numbers on the outcome of infection, as well as the effect on viral set point of increased CD4 T helper growth rate, CTL responsiveness and the rate at which CTLp and CTLe are produced were studied. We found that only when the virus has a low basic reproductive number does the number of CTLp and CD4 T helper cells at the moment of infection influence the outcome of infection. In this situation, high initial T helper and CTL numbers can switch the outcome from full-blown infection to virus control. However, this holds for virus with infectivity in a limited range, and current estimates of virus infectivity suggest that it is higher. In that case, only a vaccination protocol that increases CTL responsiveness, ideally in combination with the rate of production of CD4 T helper cells, may offer a solution as it can reduce the viral set point considerably. If brought under a certain level, the viral population might be unable to replicate any further. However, changing these parameters of the immune response is only beneficial when infection is controlled by CTL in the long term. When a CD4 lymphoproliferative response is mounted but the CTL response is not maintained, increasing the CD4 T helper growth rate is deleterious.

HIV Infections↗
PubMed2002

The persistence of CTL memory.

A very important question in immunology is to determine which factors decide whether an immune response can efficiently clear or control a viral infection, and under what circumstances we observe persistent viral replication and pathology. This paper summarises how mathematical models help us gain new insights into these questions, and explores the relationship between anti-viral therapy and long-term immunological control in HIV infection. Particular focus is given to the phenomenon of CTL memory, which I define as long-term antigen-independent persistence of CTLp. Contrary to traditional thinking, theory suggests that antigen-independent persistence of memory CTL is required to clear the primary infection, because this ensures stable and sustained immunological pressure while virus load declines. In the presence of a sustained memory response theory suggests that the CTL population is broad, directed against multiple epitopes. On the other hand, if memory CTL are not sustained in the absence of or at low levels of antigen, then the virus can establish a persistent infection. In this case, the model suggests that the CTL response is narrow, characterised by only one or a few immunodominant CTL clones. Mathematical models and experimental data suggest that HIV persistence and pathology is caused by the absence of a sustained CTL memory response, caused by the impairment of CD4 T-cell help. We show how mathematical models can help us devise therapy regimes that can restore CTL memory in HIV-infected patients and result in long-term immunological control of the virus in the absence of lifelong treatment.

HIV Infections↗
PubMed2001

Helper-dependent vs. helper-independent CTL responses in HIV infection: implications for drug therapy and resistance.

Clinical data from HIV-infected patients, as well as theoretical studies, suggest that CTL responses in the presence and absence of CD4 cell help are qualitatively different. In the presence of help, CTL responses are maintained despite very low antigenic loads and control the infection in the long term. In the absence of specific helper cell responses, CTL require high antigenic loads to be maintained, are short lived at low levels of antigen, and do not control the infection in the long term. This paper describes mathematical models analysing the dynamics of helper-dependent and helper-independent CTL in HIV infection with special focus on the dynamics during drug therapy in chronic infection. Theory suggests that a fast rate of virus spread results in high degrees of helper cell impairment which promotes the development of helper-independent CTL responses and compromised immunological control. In agreement with clinical findings, the model suggests that upon start of therapy, there is a transient increase in the level of CTL, followed by a decline to low levels once virus load has been significantly suppressed. According to the model, the presence of helper-independent CTL can promote the establishment of a helper-dependent memory response. Interestingly, this gives rise to the prediction that a relatively early stop of therapy, before the level of CTL has fallen below a threshold, can promote improved immunological control. Issues concerning the timing and duration of treatment are discussed. The CTL kinetics during drug therapy also provide new insights into the principles underlying the emergence of drug-resistant strains during the course of treatment.

CD4 Lymphocyte Count↗
PubMed2001

The role of T cell help for anti-viral CTL responses.

Cytotoxic T lymphocyte (CTL or CD8) responses are a major branch of the immune system involved in controlling viral infections. Murine models have shown that the development of effective and sustained CD8 cell responses requires CD4 T cell help. However, the precise mechanism in which CD4 cells provide help for CD8 cell responses is still controversial. In the literature, mainly two mechanisms are discussed. According to the "classical" pathway, CD4 cells secrete cytokines, such as IL-2, which promote the responsiveness of the CD8 cells. According to the "CD4-APC-CD8" pathway, CD4 cells specifically activate antigen presenting cells (APCs), and APCs specifically interact with CD8 cells, thereby delivering help. Here, we derive kinetic models in order to describe and compare both pathways of help. We find that the two pathways might have different roles in different situations. The classical pathway is more efficient at inducing CD8 cell expansion at high virus loads, while the CD4-APC-CD8 pathway is more efficient at inducing CD8 cell proliferation at low virus loads. From this, it follows that the classical pathway might be needed in order to kick-start a CD8 cell response in the acute phase of the infection, while the CD4-APC-CD8 pathway is needed in order to ensure virus clearance when virus load is reduced by the immune system. These findings have implications for the interpretation of experimental data from virus infection in helper-deficient hosts. In particular, the models offer further suggestions for the development of treatment regimes aimed at achieving immunological control of HIV infection which has been shown to crucially depend on the availability of helper cell responses.

Acute Disease↗
PubMed2001

Cytotoxic T-cell abundance and virus load in human immunodeficiency virus type 1 and human T-cell leukaemia virus type 1.

The correlation between virus load and specific cytotoxic T-lymphocyte (CTL) frequency during the chronic phase in human immunodeficiency virus type 1 (HIV-1) infection has been found to be negative in cross-sectional studies. We report here that, in infection with the related retrovirus human T-cell leukaemia virus type 1 (HTLV-1), the correlation is positive in asymptomatic carriers and zero in patients with the associated inflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We demonstrate that the direction of the correlation may depend on the efficacy of the CTL response using mathematical models. We conclude that the CTL response is effective in asymptomatic carriers of HTLV-1, but ineffective in patients with HAM/TSP. Virus-mediated impairment of specific CTL production in HIV-1 infection can account for the negative correlation observed.

Carrier State↗
PubMed2001

Viruses as antitumor weapons: defining conditions for tumor remission.

Recent research has indicated that viruses specifically infecting tumor cells could be used as an alternative therapeutic approach in cancer patients. A particular example is the adenovirus ONYX-015, which has entered clinical trials in the context of head and neck cancer. Successful therapy crucially requires an understanding about how viral and host parameters influence tumor load. The interactions between the growing tumor, the replicating virus, and possible immune responses are multifactorial and nonlinear. Hence, a complete understanding of how virus and host characteristics influence the outcome of therapy requires mathematical models. In this study, such mathematical models are presented and analyzed. The study investigates three possible scenarios that could be relevant for therapy: (a) viral cytotoxicity alone kills tumor cells; (b) a virus-specific lytic CTL response contributes to killing of infected tumor cells; (c) the virus elicits immunostimulatory signals within the tumor that promote the development of tumor-specific CTL. The models precisely define conditions required for successful therapy. They identify the parameters that need to be measured and modulated to evaluate and refine the existing therapy regimes.

Animals↗
PubMed2001

Depletion of CD4+ T cells precipitates immunopathology in immunodeficient mice infected with a noncytocidal virus.

IFN-gamma-deficient (IFN-gamma(-/-)) mice inoculated with intermediate doses of a slowly replicating strain of lymphocytic choriomeningitis virus become chronically infected. In such mice a hypercompensated CTL response is observed that partially controls virus replication. Here we have investigated whether CD4(+) Th cells are required to establish and maintain this new equilibrium. The absence of IFN-gamma does not impair the generation of IL-2-producing CD4(+) cells, and depletion of these cells precipitates severe CD8(+) T cell-mediated immunopathology in IFN-gamma(-/-) mice, indicating an important role of CD4(+) T cells in preventing this syndrome. Analysis of organ virus levels revealed a further impairment of virus control in IFN-gamma(-/-) mice following CD4(+) cell depletion. Initially the antiviral CTL response did not require CD4(+) cells, but with time an impaired reactivity toward especially the glycoprotein 33--41 epitope was noted. Enumeration of epitope-specific (glycoprotein 33--41 and nucleoprotein 396--404) CD8(+) T cells by use of tetramers gave similar results. Finally, limiting dilution analysis of CTL precursors reveal an impaired capacity to sustain this population in CD4(+)-depleted mice, especially in mice also deficient in IFN-gamma. Thus, our findings disclose that T cell help is required to sustain the expanded CTL precursor pool required in IFN-gamma(-/-) mice. This interpretation is supported by mathematical modeling that predicts an increased requirement for help in IFN-gamma(-/-) hosts similar to what is found with fast replicating virus strains in normal hosts. Thus, the functional integrity of CD8(+) effector T cells is one important factor influencing the requirement for T cell help during viral infection.

Acute Disease↗
PubMed2001

Cytotoxic T-lymphocyte memory, virus clearance and antigenic heterogeneity.

Cytotoxic T-lymphocyte (CTL) memory to viruses has traditionally been studied in an isolated setting. However, recent experiments have indicated that the presence of antigenically heterologous challenges can result in the attrition of CTL memory. Here we use mathematical models in order to explore the consequence of these dynamics for the ability of the immune system in controlling multiple infections. Mathematical models suggest that antigen-independent persistence of CTL memory is required in order to resolve and clear an infection. This ensures strong immunological pressure at low loads when the virus population declines towards extinction. If the number of antigenic stimuli exposed to the immune system crosses a threshold, we find that immunological pressure is significantly reduced at low loads and this can prevent virus clearance and reduces overall control of viral replication. Hence, exposure to many heterologous challenges reduces the ability of CTL memory to contribute to virus control. The higher the number of infections present in the host, the higher the overall virus load and the higher the total number of memory CTLs. Beyond a given threshold, addition of new viruses to the system results in accelerated loss of virus control which eventually leads to a reduction in the overall memory CTL population. These dynamics might contribute to the progressively weaker immunity observed as a result of ageing. In this context, antigenically variable pathogens expose the immune system to many heterologous challenges within a short period of time and this could result in accelerated ageing of the immune system. These results have important implications for vaccination and treatment strategies directed against viral infections.

Animals↗
PubMed2001

Role of CD8(+) lymphocytes in control of simian immunodeficiency virus infection and resistance to rechallenge after transient early antiretroviral treatment.

Transient antiretroviral treatment with tenofovir, (R)-9-(2-phosphonylmethoxypropyl)adenine, begun shortly after inoculation of rhesus macaques with the highly pathogenic simian immunodeficiency virus (SIV) isolate SIVsmE660, facilitated the development of SIV-specific lymphoproliferative responses and sustained effective control of the infection following drug discontinuation. Animals that controlled plasma viremia following transient postinoculation treatment showed substantial resistance to subsequent intravenous rechallenge with homologous (SIVsmE660) and highly heterologous (SIVmac239) SIV isolates, up to more than 1 year later, despite the absence of measurable neutralizing antibody. In some instances, resistance to rechallenge was observed despite the absence of detectable SIV-specific binding antibody and in the face of SIV lymphoproliferative responses that were low or undetectable at the time of challenge. In vivo monoclonal antibody depletion experiments demonstrated a critical role for CD8(+) lymphocytes in the control of viral replication; plasma viremia rose by as much as five log units after depletion of CD8(+) cells and returned to predepletion levels (as low as <100 copy Eq/ml) as circulating CD8(+) cells were restored. The extent of host control of replication of highly pathogenic SIV strains and the level of resistance to heterologous rechallenge achieved following transient postinoculation treatment compared favorably to the results seen after SIVsmE660 and SIVmac239 challenge with many vaccine strategies. This impressive control of viral replication was observed despite comparatively modest measured immune responses, less than those often achieved with vaccination regimens. The results help establish the underlying feasibility of efforts to develop vaccines for the prevention of AIDS, although the exact nature of the protective host responses involved remains to be elucidated.

Adenine↗
PubMed2000

Lasting effects of transient postinoculation tenofovir [9-R-(2-Phosphonomethoxypropyl)adenine] treatment on SHIV(KU2) infection of rhesus macaques.

SHIV(KU2) replicates to high levels in inoculated macaques and reproducibly causes an acute depletion of CD4(+) T cells. We evaluated the ability of treatment with the antiretroviral drug 9-R-(2-phosphonomethoxypropyl)adenine (PMPA; tenofovir), begun 7 days postinoculation, to inhibit viral replication and associated pathogenesis. Highly productive infection (plasma viral RNA > 10(6) copy eq/mL) was present and CD4 depletion had started when treatment was initiated. PMPA treatment was associated with a rapid decline in plasma viral RNA to undetectable levels, with parallel decreases in the infectivity of plasma and infectious cells in PBMCs and CSF and stabilization of CD4(+)T-cell levels. Viral dynamics parameters were calculated for the initial phase of exponential viral replication and the treatment-related decline in plasma viremia. Following cessation of treatment after 12 weeks, plasma viral RNA was detectable intermittently at low levels, and spliced viral transcripts were detected in lymph nodes. Although treatment was begun after viral dissemination, high viremia, and CD4 decreases had occurred, following withdrawal of PMPA, CD4(+) T-cell counts normalized and stabilized in the normal range, despite persistent low-level infection. No PMPA-resistance mutations were detected. These results validate the similar viral replicative dynamics of SHIV(KU2) and HIV and SIV, and also underscore the potential for long-term modulation of viral replication patterns and clinical course by perturbation of primary infection.

Adenine↗
PubMed2000

Transient antiretroviral treatment during acute simian immunodeficiency virus infection facilitates long-term control of the virus.

Experimental evidence and mathematical models indicate that CD4+ T-cell help is required to generate memory cytotoxicT-lymphocyte precursors (CTLp) that are capable of persisting without ongoing antigenic stimulation, and that such responses are necessary to clear an infection or to control it in the long term. Here we analyse mathematical models of simian immunodeficiency virus (SIV) replication in macaques, assuming that SIV impairs specific CD4+ T-cell responses. According to the models, fast viral replication during the initial stages of primary infection can result in failure to generate sufficient long-lived memory CTLp required to control the infection in the long term. Modelling of drug therapy during the acute phase of the infection indicates that transient treatment can minimize the amount of virus-induced immune impairment, allowing a more effective initial immune sensitization. The result is the development of high levels of memory CTLp that are capable of controlling SIV replication in the long term, in the absence of continuous treament. In the model, the success of treatment depends crucially on the timing and duration of antiretroviral therapy. Data on SIV-infected macaques receiving transient drug therapy during acute infection support these theoretical predictions. The data and modelling suggest that among subjects controlling SIV replication most efficiently after treatment, there is a positive correlation between cellular immune responses and virus load in the post-acute stage of infection. Among subjects showing less-efficient virus control, the correlation is negative. We discuss our findings in relation to previously published data on HIV infection.

Acute Disease↗
PubMed2000

Host factors influencing viral persistence.

With the aim of characterizing the antiviral immune response to a non-cytocidal virus, we studied the outcome of lymphocytic choriomeningitis virus infection in a number of gene knockout mouse strains. Two virus strains differing markedly in their capacity to spread and replicate inside the murine host were used. Our results reveal that very different outcomes may be observed depending on virus strain and immunocompetence of the host. Thus while CD4+ cells are not critical during the initial phase of virus control, infectious virus reappear in mice lacking CD4+ cells, B cells or CD40 ligand. Reappearance of virus is associated with impaired long-term CD8+ T-cell mediated immune surveillance, and the time to virus resurgence is inversely correlated to the replication rate of the virus. Our studies also reveal that interferon-gamma is a central cytokine, and depending on the rate of virus replication, mice lacking the ability to produce interferon-gamma may develop either a severe, mostly fatal, T-cell mediated wasting syndrome or a chronic infection characterized by long-term coexistence of antiviral cytotoxic T lymphocytes and infectious virus. Mathematical modelling indicates that these different outcomes may be explained in relatively simple mathematical terms. This suggests that modelling may be used as a means to predict critical host and virus parameters. Therefore, combining mathematical modelling with precise, quantitative, in vivo analyses looks to be a promising approach in addressing central quantitative issues in immunobiology.

Animals↗
PubMed2000

Correlates of cytotoxic T-lymphocyte-mediated virus control: implications for immunosuppressive infections and their treatment.

A very important question in immunology is to determine which factors decide whether an immune response can efficiently clear or control a viral infection, and under what circumstances we observe persistent viral replication and pathology. This paper summarizes how mathematical models help us gain new insights into these questions, and explores the relationship between antiviral therapy and long-term immunological control in human immunodeficiency virus (HIV) infection. We find that cytotoxic T lymphocyte (CTL) memory, defined as antigen-independent persistence of CTL precursors, is necessary for the CTL response to clear an infection. The presence of such a memory response is associated with the coexistence of many CTL clones directed against multiple epitopes. If CTL memory is inefficient, then persistent replication can be established. This outcome is associated with a narrow CTL response directed against only one or a few viral epitopes. If the virus replicates persistently, occurrence of pathology depends on the level of virus load at equilibrium, and this can be determined by the overall efficacy of the CTL response. Mathematical models suggest that controlled replication is reflected by a positive correlation between CTLs and virus load. On the other hand, uncontrolled viral replication results in higher loads and the absence of a correlation between CTLs and virus load. A negative correlation between CTLs and virus load indicates that the virus actively impairs immunity, as observed with HIV. Mathematical models and experimental data suggest that HIV persistence and pathology are caused by the absence of sufficient CTL memory. We show how mathematical models can help us devise therapy regimens that can restore CTL memory in HIV patients and result in long-term immunological control of the virus in the absence of life-long treatment.

AIDS Vaccines↗
PubMed2000

Defining CTL-induced pathology: implications for HIV.

The relationship between virus and host cells is multifactorial and nonlinear. This indicates that the effect of an immune response on infection can lead to several different outcomes. These include severe immunopathology. We seek to define properties of CTL-induced pathology in viral infections and examine the implications for HIV disease progression. We find that CTL-induced pathology is observed if the rate of viral replication is fast relative to the CTL responsiveness of the host. Theoretical predictions are consistent with empirical data on LCMV infection. These conditions are also sufficient to induce pathology in HIV infection. However, the absence of HIV-specific CTL can result in an equivalent depletion of the CD4 T cell pool as a consequence of the short life span of activated T cells. A mathematical model describing the evolution of HIV coreceptor usage in the context of lytic and nonlytic CD8 cell responses might account for the relatively long time span required to result in disease. Viral evolution toward parameter ranges allowing CTL-induced pathology is difficult to achieve. It requires the emergence of fast viral replication together with escape from nonlytic CTL responses. However, according to the model, fast viral replication can result in the evolution of virus strains that are susceptible to chemokine-mediated inhibition of viral replication.

Biological Evolution↗
PubMed2000

HIV-1 dynamics revisited: biphasic decay by cytotoxic T lymphocyte killing?

The biphasic decay of blood viraemia in patients being treated for human immunodeficiency virus type 1 (HIV-1) infection has been explained as the decay of two distinct populations of cells: the rapid death of productively infected cells followed by the much slower elimination of a second population the identity of which remains unknown. Here we advance an alternative explanation based on the immune response against a single population of infected cells. We show that the biphasic decay can be explained simply, without invoking multiple compartments: viral load falls quickly while cytotoxic T lymphocytes (CTL) are still abundant, and more slowly as CTL disappear. We propose a method to test this idea, and develop a framework that is readily applicable to treatment of other infections.

HIV Infections↗
PubMed2000

A new theory of cytotoxic T-lymphocyte memory: implications for HIV treatment.

We use simple mathematical models to examine the dynamics of primary and secondary cytotoxic T-lymphocyte (CTL) responses to viral infections. In particular, we are interested in conditions required to resolve the infection and to protect the host upon secondary challenge. While protection against reinfection is only effective in a restricted set of circumstances, we find that resolution of the primary infection requires persistence of CTL precursors (GTLp), as well as a fast rate of activation of the CTLp. Since these are commonly the defining characteristics of CTL memory, we propose that CTL memory may have evolved in order to clear the virus during primary challenge. We show experimental data from lymphocytic choriomeningitis virus infection in mice, supporting our theory on CTL memory. We adapt our models to HIV and find that immune impairment during the primary phase of the infection may result in the failure to establish CTL memory which in turn leads to viral persistence. Based on our models we suggest conceptual treatment regimes which ensure establishment of CTL memory. This would allow the immune response to control HIV in the long term in the absence of continued therapy.

Animals↗