Model Of HIV Pathogenesis Research Articles

Dynamics of Two Delays Differential Equations Model of HIV Pathogenesis with Absorption and Saturation Incidence

Dynamics of Two Delays Differential Equations Model of HIV Pathogenesis with Absorption and Saturation Incidence

Dynamics of an HIV pathogenesis Model with Absorption and Saturation Incidence

In this paper, the dynamics of an HIV infection model with absorption and saturation incidence are proposed and analyzed. Further, we introduce a time delay to the model, which describes a time between infected cells and excretion of the viral particles. This model is used to explain existence, characteristic equations, and stability of infected and disease free steady states. Numerical simulations are provided to illustrate the theoretical results.

On dynamics of an HIV pathogenesis model with full logistic target cell growth and cure rate

The objective of this paper is to discuss the dynamics of an HIV pathogenesis model with full logistic target cell growth of uninfected T cells and cure rate of infected T cells. Local and global dynamics of both infection-free and infected equilibrium points are rigorously established. It is found that if basic reproduction number R 0 ≤1, the infection is cleared from T cells and if R 0 >1, the HIV infection persists. Also, we have carried out numerical simulations to verify the results. The existence of non-trivial periodic solution is also studied by means of numerical simulation. Therefore, we find a parameter region where infected equilibrium point is globally stable to make the model biologically significant. From the overall study, it is found that proliferation of T cells cannot be ignored during the study of HIV dynamics for better results and we can focus on a treatment policy which can control the parameters of the model in such a way that the basic reproduction number remains less than or equal to one.

A stochastic delay model of HIV pathogenesis with reactivation of latent reservoirs

Abstract In this paper, we propose a stochastic HIV model with latency to describe the factors that are responsible for extinction and persistence of the infection. This model incorporates latent period of reservoirs that inhibits the eradication of the virus. It is shown that this model leads naturally to a stochastic system of differential delay equations. We derived the global existence, positivity and boundedness properties of solutions of the proposed stochastic system. Analyzing the model, sufficient conditions for the eradication and the persistence of the disease are also obtained. Furthermore, numerical simulations are performed to study the impact of several strategies of drug therapy on the persistence and the extinction of HIV virus. Our results constitute an important step towards control strategies to reduce HIV infection.

Modified Newcastle Disease virus as an improved vaccine vector against Simian Immunodeficiency virus

SIV infection in macaques is a relevant animal model for HIV pathogenesis and vaccine study in humans. To design a safe and effective vaccine against HIV, we evaluated the suitability of naturally-occurring avirulent Newcastle disease virus (NDV) strains and several modified versions of NDV as vectors for the expression and immunogenicity of SIV envelope protein gp160. All the NDV vectors expressed gp160 protein in infected cells. The gp160 expressed by these vectors formed oligomers and was incorporated into the NDV envelope. All the NDV vectors expressing gp160 were attenuated in chickens. Intranasal immunization of guinea pigs with modified NDV vectors such as rNDV-APMV-2CS/gp160 and rNDV-APMV-8CS/gp160 (NDV strain LaSota containing the cleavage site sequences of F protein of avian paramyxovirus (APMV) serotype 2 and 8, respectively), and rNDV-BC-F-HN/gp160 (NDV strain BC containing LaSota F cleavage site and LaSota F and HN genes) elicited improved SIV-specific humoral and mucosal immune responses compared to other NDV vectors. These modified vectors were also efficient in inducing neutralizing antibody responses to tier 1 A SIVmac251.6 and tier 1B SIVmac251/M766 strains. This study suggests that our novel modified NDV vectors are safe and immunogenic and can be used as vaccine vector to control HIV.

Regulatory and Helper Follicular T Cells and Antibody Avidity to Simian Immunodeficiency Virus Glycoprotein 120.

T follicular regulatory cells (TFR) are a suppressive CD4(+) T cell subset that migrates to germinal centers (GC) during Ag presentation by upregulating the chemokine receptor CXCR5. In the GC, TFR control T follicular helper cell (TFH) expansion and modulate the development of high-affinity Ag-specific responses. In this study, we identified and characterized TFR as CXCR5(+)CCR7(-) "follicular" T regulatory cells in lymphoid tissues of healthy rhesus macaques, and we studied their dynamics throughout infection in a well-defined animal model of HIV pathogenesis. TFR were infected by SIVmac251 and had comparable levels of SIV DNA to CXCR5(-)CCR7(+) "T zone" T regulatory cells and TFH. Contrary to the SIV-associated TFH expansion in the chronic phase of infection, we observed an apparent reduction of TFR frequency in cell suspension, as well as a decrease of CD3(+)Foxp3(+) cells in the GC of intact lymph nodes. TFR frequency was inversely associated with the percentage of TFH and, interestingly, with the avidity of the Abs that recognize the SIV gp120 envelope protein. Our findings show changes in the TFH/TFR ratio during chronic infection and suggest possible mechanisms for the unchecked expansion of TFH cells in HIV/SIV infection.

On global stability of an HIV pathogenesis model with cure rate

In this paper, applying both Lyapunov function techniques and monotone iterative techniques, we establish new sufficient conditions under which the infected equilibrium of an HIV pathogenesis model with cure rate is globally asymptotically stable. By giving an explicit expression for eventual lower bound of the concentration of susceptible CD4+ T cells, we establish an affirmative partial answer to the numerical simulations investigated in the recent paper [Liu, Wang, Hu and Ma, Global stability of an HIV pathogenesis model with cure rate, Nonlinear Analysis RWA (2011) 12: 2947–2961]. Our monotone iterative techniques are applicable for the small and large growth rate in logistic functions for the proliferation rate of healthy and infected CD4+ T cells. Copyright © 2014 John Wiley & Sons, Ltd.

Treatment of chronically FIV-infected cats with suberoylanilide hydroxamic acid

Feline immunodeficiency virus (FIV) is a naturally-occurring, large animal model of lentiviral-induced immunodeficiency syndrome, and has been used as a model of HIV pathogenesis and therapeutic interventions. HIV reservoirs in the form of latent virus remain the primary roadblock to viral eradication and cure, and FIV has been previously established an animal model of lentiviral latency. The goal of this study was to determine whether administration of the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) to aviremic, chronically FIV-infected cats would induce latent viral reactivation in vivo. A proof-of-concept experiment in a Transwell co-culture system demonstrated the ability of SAHA to reactivate latent virus which was replication competent and able to infect naïve cells. Oral SAHA (250mg/m2) was administered with food to four asymptomatic, experimentally FIV-infected cats and one uninfected control cat, and a limited pharmacokinetic and pharmacodynamic analysis was performed. A statistically significant increase in cell-associated FIV RNA was detected in the cat with the greatest serum SAHA exposure, and cell-free viral RNA was detected at one time point in the three cats that achieved the highest levels of SAHA in serum. Interestingly, there was a significant decrease in viral DNA burden at 2h post drug administration in the same three cats. Though the sample size is small and the drug response was modest, this study provides evidence that in vivo treatment of FIV-infected cats with the HDACi SAHA can induce viral transcriptional reactivation, which may be dependent upon the concentration of SAHA achieved in blood. Importantly, alternative putative antilatency therapy drugs, and multimodal drug combinations, could be studied in this in vivo system. The FIV/cat model provides a unique opportunity to test novel therapeutic interventions aimed at eradicating latent virus in vivo.

Construction of SHIVs expressing quaternary neutralization epitopes in Env and mimicking the neutralization phenotype of typical HIV-1 isolates

Background Infection of macaques with chimeric Simian/Human Immunodeficiency Viruses (SHIVs) provides a powerful model for HIV pathogenesis and vaccine development. A limitation of the SHIVs routinely used for vaccine studies, e.g. SHIV-1157ipd3N4, SHIV-SF162P3, and SHIV-BaL, is that they don’t express quaternary neutralization epitopes (QNEs) that are targets of broadly neutralizing antibodies like PG9, PG16, and CAP256 sera. We sought to introduce the QNEs into functional SHIVs to study how such antibodies develop during infection and help guide the creation of antigens capable of eliciting such antibodies.

Global stability of an HIV pathogenesis model with cure rate

In this paper, we consider an HIV pathogenesis model including cure rate and the full logistic proliferation term of CD4 + T cells in healthy and infected populations. Let N be the number of virus released by each productive infected CD4 + T cell. The critical number N crit that ensures the existence of the positive equilibrium is obtained. We further show that if N ≤ N crit , then there exists a unique uninfected equilibrium point E 0 that is locally asymptotically stable. If N > N crit , then the system is persistent and the only infected steady state E ∗ is globally asymptotically stable in the feasible region. Numerical simulations are presented to illustrate the obtained main results. Moreover, we find that there exist periodic solutions when the infected steady state E ∗ is unstable.

Morphine Potentiates Neuropathogenesis of SIV Infection in Rhesus Macaques

Despite the advent of antiretroviral therapy, complications of HIV-1 infection with concurrent drug abuse are an emerging problem. Opiates are well known to modulate immune responses by preventing the development of cell-mediated immune responses. Their effect on the pathogenesis of HIV-1 infection however remains controversial. Using the simian immunodeficiency virus/macaque model of HIV pathogenesis, we sought to explore the impact of morphine on disease progression and pathogenesis. Sixteen rhesus macaques were divided into two groups; four were administered saline and 12 others morphine routinely. Both groups of animals were then inoculated with SIVmacR71/17E and followed longitudinally for disease pathogenesis. The morphine group (M+V) exhibited a trend towards higher mortality rates and retardation in weight gain compared to the virus-alone group. Interestingly, a subset of M+V animals succumbed to disease within weeks post-infection. These rapid progressors also exhibited a higher incidence of other end-organ pathologies. Despite the higher numbers of circulating CD4+ and CD8+ T cells in the M+V group, CD4/CD8 ratios between the groups remained unchanged. Plasma and CSF viral load in the M+V group was at least a log higher than the control group. Similarly, there was a trend toward increased virus build-up in the brains of M+V animals compared with controls. A novel finding of this study was the increased influx of infected monocyte/macrophages in the brains of M+V animals.

The Symmetrical Immune Network Theory and a New HIV Vaccine Concept

AbstractThe symmetrical immune network theory is based on Jerne’s network hypothesis. An improved version of the theory is presented. The theory is characterized by symmetrical stimulatory, inhibitory and killing interactions between idiotypic and antiidiotypic immune system components. In this version killing is ascribed to IgM antibodies, while IgG antibodies are stimulatory. In the symmetrical immune network theory T cells make specific T cell factors, that have a single V region, and are cytophilic for non-specific accessory cells (A cells, including macrophages and monocytes) and play a role in the system switching between stable steady states. A recurring theme in the theory is the concept of co selection. Co-selection is the mutual positive selection of individual members from within two diverse populations, such that selection of members within each population is dependent on interaction with (recognition of) one or more members within the other population. Prior to exposure to an antigen, antigen-specific and antiidiotypic T cells are equally diverse. This equality is a form of symmetry. Immune responses with the production of IgG involve co selection of the antigen-specific and antiidiotypic classes with the breaking of this diversity symmetry, while induction of unresponsiveness involves co-selection without the breaking of diversity symmetry. The theory resolves the famous I-J paradox of the 1980s, based on co selection of helper T cells with some affinity for MHC class II and suppressor T cells that are anti-anti-MHC class II. The theory leads to three experimentally testable predictions concerning I-J. The theory includes a model for HIV pathogenesis, and suggests that polyclonal IgG from many donors given in immunogenic form may be an effective vaccine for protection against infection with HIV. Surprisingly, a mathematical model that simulates the autonomous dynamics of the system is the same as one that models a previously described neural network.

Analysis of the dynamics of a delayed HIV pathogenesis model

In this paper, considering full Logistic proliferation of CD4 + T cells, we study an HIV pathogenesis model with antiretroviral therapy and HIV replication time. We first analyze the existence and stability of the equilibrium, and then investigate the effect of the time delay on the stability of the infected steady state. Sufficient conditions are given to ensure that the infected steady state is asymptotically stable for all delay. Furthermore, we apply the Nyquist criterion to estimate the length of delay for which stability continues to hold, and investigate the existence of Hopf bifurcation by using a delay τ as a bifurcation parameter. Finally, numerical simulations are presented to illustrate the main results.

The oxidative stress-induced niacin sink (OSINS) model for HIV pathogenesis

Although several specific micronutrient deficiencies are associated with disease progression and increased mortality risk in HIV/AIDS, and even a simple multivitamin/mineral supplement can prolong survival, this is typically viewed merely as nutritional support of the immune system, and only necessary if there are deficiencies to be rectified. However, the reality is more complex. Several striking nutrient-related metabolic abnormalities have been consistently documented in HIV infection. One is chronic oxidative stress, including a drastic depletion of cysteine from the glutathione pool, and a progressive decline of serum selenium that is correlated with disease progression and mortality. Another is decreased blood levels of tryptophan, with an associated intracellular niacin deficiency. Tryptophan depletion or “deletion” by induction of indoleamine-2,3-dioxygenase (IDO), the first step in oxidative tryptophan metabolism, is a known mechanism for immune suppression that is of critical importance in cancer and pregnancy, and, potentially, in HIV/AIDS. Existing evidence supports the hypothesis that these nutrient-related metabolic abnormalities in HIV infection regarding antioxidants, selenium, sulfur, tryptophan and niacin are interrelated, because HIV-associated oxidative stress can induce niacin/NAD+ depletion via activation of poly(ADP-ribose) polymerase (PARP), which could lead to tryptophan oxidation for compensatory de novo niacin synthesis, thereby contributing to immune tolerance and T-cell loss via tryptophan deletion and PARP-induced cell death. This “oxidative stress-induced niacin sink” (OSINS) model provides a mechanism whereby the oxidative stress associated with HIV infection can contribute to immunosuppression via tryptophan deletion. This model is directly supported by evidence that antioxidants can counteract indoleamine-2,3-dioxygenase (IDO), providing the critical link between oxidative stress and tryptophan metabolism proposed here. The OSINS model can be used to guide the design of nutraceutical regimens that can effectively complement antiretroviral therapy for HIV/AIDS.

A stochastic model of the dynamics of HIV under a combination therapeutic intervention

Drug resistance to single therapeutic treatment in HIV infected individuals has promoted research into combined treatments. In this paper we propose a stochastic model under combined therapeutic treatment by extending the model of HIV pathogenesis under treatment by anti-viral drugs given in [Perelson AS, Neumann AU, Markowits M, Leonard JM & Ho DD, 1996, HIV-1 dynamics in vivo virion clearance rate, infected cell life span, and viral generation time, Science New Series, 271, pp. 1582{1586]. Variance and co-variance structures of variables are obtainable via this approach in addition to the mean numbers of free HIV, infectious free HIV and non-infectious free HIV that were obtained by Perelson et al. Comparing simulated data for before and after treatment indicates the importance of combined treatment and its overall eect(s).

Oscillatory viral dynamics in a delayed HIV pathogenesis model

We consider an HIV pathogenesis model incorporating antiretroviral therapy and HIV replication time. We investigate the existence and stability of equilibria, as well as Hopf bifurcations to sustained oscillations when drug efficacy is less than 100%. We derive sufficient conditions for the global asymptotic stability of the uninfected steady state. We show that time delay has no effect on the local asymptotic stability of the uninfected steady state, but can destabilize the infected steady state, leading to a Hopf bifurcation to periodic solutions in the realistic parameter ranges.

Toll-Like Receptor Ligands Induce Human T Cell Activation and Death, a Model for HIV Pathogenesis

BackgroundRecently, heightened systemic translocation of microbial products was found in persons with chronic HIV infection and this was linked to immune activation and CD4+ T cell homeostasis.MethodologyWe examined here the effects of microbial Toll-like receptor (TLR) ligands on T cell activation in vitro.Conclusions/FindingsWe show that exposure to TLR ligands results in activation of memory and effector CD4+ and CD8+ T cells. After exposure to each of 8 different ligands that activate TLRs 2, 3, 4, 5, 7, 8, and 9, CD8+ T cells are activated and gain expression of the C type lectin CD69 that may promote their retention in lymphoid tissues. In contrast, CD4+ T cells rarely increase CD69 expression but instead enter cell cycle. Despite activation and cell cycle entry, CD4+ T cells divide poorly and instead, disproportionately undergo activation-induced cell death. Systemic exposure to TLR agonists may therefore increase immune activation, effector cell sequestration in lymphoid tissues and T cell turnover. These events may contribute to the pathogenesis of immune dysfunction and CD4+ T cell losses in chronic infection with the human immunodeficiency virus.

Immune activation and inflammation in HIV‐1 infection: causes and consequences

Thorough research on HIV is progressively enabling us to understand the intricate mechanisms that link HIV-1 infection to the onset of immunodeficiency. The infection and depletion of CD4(+) T cells represent the most fundamental events in HIV-1 infection. However, in recent years, the role played by chronic immune activation and inflammation in HIV pathogenesis has become increasingly apparent: quite paradoxically, immune activation levels are directly associated with HIV-1 disease progression. In addition, HIV-1-infected patients present intriguing similarities with individuals of old age: their immune systems are characterized by a loss of regenerative capacity and an accumulation of ageing T cells. In this review, we discuss the potential reasons for the establishment of sustained immune activation and inflammation from the early stages of HIV-1 infection, as well as the long-term consequences of this process on the host immune system and health. A simplified model of HIV pathogenesis is proposed, which links together the three major facets of HIV-1 infection: the massive depletion of CD4(+) T cells, the paradoxical immune activation and the exhaustion of regenerative capacity.

SHIV-KB9 Infection of Rhesus Monkeys Does Not Always Cause Disease-Contribution of Host Immune Factors and Thymic Output

Simian-human immunodeficiency virus (SHIV) infection in the macaque is a model of HIV pathogenesis. KB9, a molecular clone of SHIV 89.6P, induced rapid and profound CD4+ T cell loss in rhesus monkeys, followed by partial recovery in some. We describe another clinical outcome after intravenous SHIV-KB9 inoculation in two of six infected rhesus macaques: lack of signs of immunodeficiency with sustained CD4+ T cell counts, despite virus load levels similar to those of the animals with CD4+ lymphocyte decline. To dissect the role of host factors in determining pathogenicity of this viral clone, humoral and cellular immune responses were studied. Differences in CD8+ T cell effector responses and activation profiles and in thymic output, but not in specific antibody production, were observed in animals with different disease outcomes during acute infection. Thymic involvement may thus be a critical factor in determining disease progression.

The infiltration kinetics of simian immunodeficiency virus-specific T cells drawn to sites of high antigenic stimulation determines local in vivo viral escape.

Despite vigorous cell-mediated immune responses to human and simian immunodeficiency viruses (HIV/SIV) the immune system is unable to clear latently infected resting T cells. These infected cells are reactivated by antigenic stimulation, leading to viral replication. By using the SIV/macaque model of HIV pathogenesis, the dynamics of T cell infiltration into delayed type hypersensitivity sites specific for the purified protein derivative of bacillus Calmette-Guérin have been studied. Early viral mRNA synthesis coincided with the infiltration of antigen-specific T cells. When the infiltration of anti-SIV-specific T cells was rapid compared with the kinetics of viral assembly, the sites were sterilized before the transition to late viral mRNA synthesis occurred. When their infiltration was slow, ephemeral foci of replication were identified. These findings were paralleled by plasma viremia; low viremia coincided with rapid sterilization of the delayed type hypersensitivity sites, whereas high load was found in association with local replication and delayed sterilization. These data suggest that although effective local control of SIV is possible once antiviral T lymphocytes have arrived on site, the slower deployment of these T cells may allow the virus to escape and thus to reseed the pool of memory T cells.